Phenoxy acetic acids as ppar delta activators

ABSTRACT

The present invention describes phenoxy-acetic acids and pharmaceutical compositions containing the same and methods of using the same. The phenoxy-acetic acids are activators of PPAR-δ and should be useful for treating conditions mediated by the same.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation application of U.S. patentapplication Ser. No. 13/080,425, which is a divisional application ofU.S. patent application Ser. No. 11/917,811, which is the United Statesnational stage application, under 35 U.S.C. §371, of PCT Application No.PCT/EP2006/063703, filed Jun. 29, 2006, which in turn claims priority toEuropean Patent Application Nos. 05105937.6, filed Jun. 30, 2005, and05112755.3, filed Dec. 22, 2005. Each of the foregoing applications isincorporated by reference as though fully set forth herein in itsentirety.

FIELD OF THE INVENTION

The present invention relates to novel phenoxy-acetic acids,pharmaceuticals comprising the same, and methods of using the same. Thephenoxy-acetic acids are activators of peroxisome proliferator-activatedreceptors (PPAR)-δ.

BACKGROUND OF THE INVENTION

Coronary artery disease (CAD) is the major cause of death in Type 2diabetic and metabolic syndrome patients (i.e., patients that fallwithin the ‘deadly quartet’ category of impaired glucose tolerance,insulin resistance, hypertriglyceridaemia and/or obesity).

The hypolipidaemic fibrates and antidiabetic thiazolidinedionesseparately display moderately effective triglyceride-loweringactivities, although they are neither potent nor efficacious enough tobe a single therapy of choice for the dyslipidaemia often observed inType 2 diabetic or metabolic syndrome patients. The thiazolidinedionesalso potently lower circulating glucose levels of Type 2 diabetic animalmodels and humans. However, the fibrate class of compounds are withoutbeneficial effects on glycaemia. Studies on the molecular actions ofthese compounds indicate that thiazolidinediones and fibrates exerttheir action by activating distinct transcription factors of theperoxisome proliferator activated receptor (PPAR) family, resulting inincreased and decreased expression of specific enzymes andapolipoproteins respectively, both key-players in regulation of plasmatriglyceride content.

PPAR-δ activation was initially reported not to be involved inmodulation of glucose or triglyceride levels. (Berger et al., J. Biol.Chem. 1999, 274, 6718-6725). Later it was shown that PPAR-δ activationleads to increased levels of HDL cholesterol in db/db mice (Leibowitz etal., FEBS letters 2000, 473, 333-336). Further, a PPAR-δ agonist whendosed to insulin-resistant middle-aged obese rhesus monkeys caused adramatic dose-dependent rise in serum HDL cholesterol while lowering thelevels of small dense LDL, fasting triglycerides and fasting insulin(Oliver et al., PNAS 2001, 98, 5306-5311). The same paper also showedthat PPAR-δ activation increased the reverse cholesterol transporterATP-binding cassette A1 and induced apolipoprotein A1-specificcholesterol efflux. The involvement of PPAR-δ in fatty acid oxidation inmuscles was further substantiated in PPAR-α knock-out mice. Muoio et al.(J. Biol. Chem. 2002, 277, 26089-26097) showed that the high levels ofPPAR-δ in skeletal muscle can compensate for deficiency in PPAR-α. Inaddition to the effects on cholesterol homeostasis, PPARδ treatment wasobserved to lower plasma glucose and insulin and improve insulinsensitivity in diabetic ob/ob and db/db mice and high fat diet inducedinsulin resistant mice (PNAS 2003, 100, 15924-15929; PNAS 2006, 103,3444-3449). Taken together these observations suggest that PPAR-δactivation is useful in the treatment and prevention of Type 2 diabetes,cardiovascular diseases and conditions including atherosclerosis,hypertriglyceridemia, and mixed dyslipidaemia (WO 01/00603).

A number of PPAR-δ compounds have been reported to be useful in thetreatment of hyperglycemia, hyperlipidemia and hypercholesterolemia (WO02/59098, WO 01/603, WO 01/25181, WO 02/14291, WO 01/79197, WO 99/4815,WO 97/28149, WO 98/27974, WO 97/28115, WO 97/27857, WO 97/28137, and WO97/27847). WO 2004093879, WO 2004092117, WO 2004080947, WO 2004080943,WO 2004073606, WO 2004063166, WO 2004063165, WO 2003072100, WO2004060871, WO 2004005253, WO 2003097607, WO 2003035603, WO 2004000315,WO 2004000762, WO 2003074495, WO 2002070011, WO 2003084916, US20040209936, WO 2003074050, WO 2003074051, WO 2003074052, JP 2003171275,WO 2003033493, WO 2003016291, WO 2002076957, WO 2002046154, WO2002014291, WO 2001079197, WO 2003024395, WO 2002059098, WO 2002062774,WO 2002050048, WO 2002028434, WO 2001000603, WO 2001060807, WO 9728149,WO 2001034200, WO 9904815, WO 200125226, WO 2005097098; WO 2005097762;WO 2005097763.

Glucose lowering as a single approach does not overcome themacrovascular complications associated with Type 2 diabetes andmetabolic syndrome. Novel treatments of Type 2 diabetes and metabolicsyndrome must therefore aim at lowering both the overthypertriglyceridaemia associated with these syndromes as well asalleviation of hyperglycaemia. This indicates that research forcompounds displaying various degree of PPAR-δ activation should lead tothe discovery of efficacious triglyceride and/or cholesterol and/orglucose lowering drugs that have great potential in the treatment ofdiseases such as type 2 diabetes, dyslipidemia, syndrome X (includingthe metabolic syndrome, i.e., impaired glucose tolerance, insulinresistance, hypertrigyceridaemia and/or obesity), cardiovasculardiseases (including atherosclerosis) and hypercholesteremia.

SUMMARY OF THE INVENTION

In an aspect, the present invention provides novel phenoxy-acetic acidsor pharmaceutically acceptable salts thereof that are useful as PPAR-δactivators.

In another aspect, the present invention provides novel pharmaceuticalcompositions comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one of the compounds of thepresent invention or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a novel method oftreating type 2 diabetes comprising administering to a patient in needthereof a therapeutically effective amount of at least one compound ofthe present invention or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a novel method oftreating a disease comprising administering to a patient in need thereofa therapeutically effective amount of at least one compound of thepresent invention or a pharmaceutically acceptable salt thereof, whereinthe disease is selected from dyslipidemia, syndrome X (including themetabolic syndrome, e.g., hypertension, impaired glucose tolerance(IGT), insulin resistance, hypertrigyceridaemia, and obesity),cardiovascular diseases (e.g., atherosclerosis, coronary artery disease,and myocardial ischemia), hyperglycemia, hyperlipidemia, andhypercholesterolemia.

In another aspect, the present invention provides a novel method oftreating a disease comprising administering to a patient in need thereofa therapeutically effective amount of at least one compound of thepresent invention or a pharmaceutically acceptable salt thereof, whereinthe disease is selected from non-insulin requiring Type 2 diabetes toinsulin requiring Type 2 diabetes, decreasing apoptosis in mammaliancells (e.g., beta cells of Islets of Langerhans), renal diseases (e.g.,glomerulonephritis, glomerulosclerosis, nephrotic syndrome, andhypertensive nephrosclerosis), improving cognitive functions indementia, treating diabetic complications, psoriasis, polycystic ovariansyndrome (PCOS), prevention and treatment of bone loss (e.g.,osteoporosis), and lowering the bio-markers of atherosclerosis (e.g.,c-reactive protein (CRP), TNF-α, and IL-6).

In another aspect, the present invention provides novel compounds foruse in therapy.

In another aspect, the present invention provides the use of novelcompounds for the manufacture of a medicament for the treatment of type2 diabetes.

These and other objects, which will become apparent during the followingdetailed description, have been achieved by the inventors' discoverythat compounds of formula I:

or pharmaceutically acceptable salts thereof, are PPAR-δ activators.

DESCRIPTION OF THE INVENTION

In a first embodiment, the present invention provides a novel compoundof formula I:

or a pharmaceutically acceptable salt thereof, wherein:

X is selected from O, S, OCH₂, and SCH₂;

X¹ is O or S;

R¹ is selected from H, C₁₋₈ alkyl, C₂₋₈ alkenyl, aryl, heteroaryl, C₃₋₁₀cycloalkyl, and a heterocyclyl, wherein each R¹ group is substitutedwith 0-4 R^(1a);

R^(1a), at each occurrence, is selected from S substituted with 0-1R^(1b), O substituted with 0-1 R^(1b), halogen, NH₂ substituted with 0-2R^(1b), —CN, NO₂, C₁₋₆ alkyl substituted with 0-3 R^(1b), C₂₋₆ alkenylsubstituted with 0-2 R^(1b), C₂₋₆alkynyl substituted with 0-2 R^(1b),aryl substituted with 0-2 R^(1b), heteroaryl substituted with 0-2R^(1b), C₃₋₁₀ cycloalkyl substituted with 0-2 R^(1b), and heterocyclesubstituted with 0-2 R^(1b);

R^(1b), at each occurrence, is selected from S substituted with 0-1R^(1c), O substituted with 0-1 R^(1c), halogen, methanesulfonyl, NH₂substituted with 0-2 R^(1c), —CN, NO₂, C₁₋₆ alkyl substituted with 0-3R^(1c), C₂₋₆alkenyl substituted with 0-2 R^(1c), aryl substituted with0-2 R^(1c), heteroaryl substituted with 0-2 R^(1c), C₃₋₁₀ cycloalkylsubstituted with 0-2 R^(1c), and a heterocycle substituted with 0-2R^(1c);

R^(1c), at each occurrence, is selected from S substituted with 0-1R^(1d), O substituted with 0-1 R^(1d), halogen, NH₂ substituted with 0-2R^(1d), —CN, NO₂, C₁₋₆ alkyl substituted with 0-2 R^(1d), C₂₋₆alkenylsubstituted with 0-2 R^(1d), aryl substituted with 0-2 R^(1d),heteroaryl substituted with 0-2 R^(1d), C₃₋₁₀ cycloalkyl substitutedwith 0-2 R^(1d), and a heterocycle substituted with 0-2 R^(1d);

R^(1d), at each occurrence, is selected from OH, SH, S, O, halogen, NH₂,—CN, NO₂, C₁₋₆ alkyl, C₂₋₆alkenyl, aryl, CF₃, and OCF₃;

R² is selected from —C≡C—R^(2a), —CH═CH—R^(2a), aryl substituted with0-3 R^(2a), and heteroaryl substituted with 0-3 R^(2a);

R^(2a), at each occurrence, is selected from S substituted with 0-1R^(2b), O substituted with 0-1 R^(2b), halogen, NH₂ substituted with 0-2R^(2b), —CN, NO₂, C₁₋₆ alkyl substituted with 0-2 R^(2b), C₂₋₆ alkenylsubstituted with 0-2 R^(2b), aryl substituted with 0-2 R^(2b),heteroaryl substituted with 0-2 R^(2b), C₃₋₁₀ cycloalkyl substitutedwith 0-2 R^(2b), and a heterocycle substituted with 0-2;

R^(2b), at each occurrence, is selected from S substituted with 0-1R^(2c), O substituted with 0-1 R^(2c), halogen, methanesulfonyl, NH₂substituted with 0-2 R^(2c), —CN, NO₂, C₁₋₆alkyl substituted with 0-2R^(2c), C₂₋₆alkenyl substituted with 0-2 R^(2c), aryl substituted with0-2 R^(2c), heteroaryl substituted with 0-2 R^(2c), C₃₋₁₀ cycloalkylsubstituted with 0-2 R^(2c), and a heterocycle substituted with 0-2R^(2c);

R^(2c), at each occurrence, is selected from S substituted with 0-1R^(2d), O substituted with 0-1 R^(2d), halogen, NH₂ substituted with 0-2R^(2d), —CN, NO₂, C₁₋₆alkyl substituted with 0-2 R^(2d), C₂₋₆ alkenylsubstituted with 0-2 R^(2d), aryl substituted with 0-2 R^(2d),heteroaryl substituted with 0-2 R^(2d), C₃₋₁₀ cycloalkyl substitutedwith 0-2 R^(2d), and a heterocycle substituted with 0-2 R^(2d)

R^(2d), at each occurrence, is selected from OH, SH, S, O, halogen, NH₂,—CN, NO₂, C₁₋₆ alkyl, C₂₋₆alkenyl, aryl, CF₃, and OCF₃;

R³ is selected from halogen and C₁₋₆ alkyl substituted with 0-2 R^(3a);

R^(3a), at each occurrence, is selected from OH, O, S, halogen, C(O)NH₂,C(O)NH—C₁₋₄ alkyl, and C(O)N(C₁₋₄ alkyl)₂;

alternatively, R³ and R^(5e) combine to form a 5, 6, or 7 membered ringconsisting of carbon atoms and 0-2 heteroatoms selected from O, N, andS(O)₀₋₂ and there are 0-2 ring double bonds in the bridging portionformed by R³ and R^(5e);

R^(4a), at each occurrence, is selected from H, halogen, and C₁₋₆ alkylsubstituted with 0-2 R^(4d);

R^(4d), at each occurrence, is selected from OH, O, halogen, NH₂,NH—C₁₋₄ alkyl, and N(C₁₋₄ alkyl)₂;

R^(4b), at each occurrence, is selected from H, halogen, and C₁₋₆ alkylsubstituted with 0-2 R^(4e);

R^(4e), at each occurrence, is selected from OH, O, halogen, NH₂,NH—C₁₋₄ alkyl, and N(C₁₋₄ alkyl)₂;

R^(4c), at each occurrence, is selected from H, halogen, and C₁₋₆ alkylsubstituted with 0-2 R^(4f);

R^(4f), at each occurrence, is selected from OH, O, halogen, NH₂,NH—C₁₋₄ alkyl, and N(C₁₋₄ alkyl)₂;

R^(5a), at each occurrence, is selected from H, halogen, CH₃, and CH₂CH₃;

R^(5b), at each occurrence, is selected from H, halogen, CH₃, and CH₂CH₃;

R^(5c), at each occurrence, is selected from H, halogen, CH₃, and CH₂CH₃;

R^(5d), at each occurrence, is selected from H, halogen, CH₃, and CH₂CH₃; and,

R^(5e), at each occurrence, is selected from H, halogen, CH₃, and CH₂CH₃.

In another embodiment, the present invention provides a novel compoundof formula I or a pharmaceutically acceptable salt thereof, wherein:

X is selected from O, S, OCH₂, and SCH₂;

X¹ is O or S;

R¹ is selected from H, C₁₋₈ alkyl, C₂₋₈ alkenyl, aryl, 5-10 memberedheteroaryl consisting of carbon atoms and 1-4 heteroatoms selected fromO, N, and S(O)₀₋₂, C₃₋₁₀ cycloalkyl, and a 3-8 membered heterocycleconsisting of carbon atoms and 1-3 heteroatoms selected from O, N, andS(O)₀₋₂, wherein each R¹ group is substituted with 0-4 R^(1a);

R^(1a), at each occurrence, is selected from OH substituted with 0-1R^(1b), SH substituted with 0-1 R^(1b), S, O, halogen, NH₂ substitutedwith 0-2 R^(1b), —CN, NO₂, C₁₋₆alkyl substituted with 0-3 R^(1b),C₂₋₆alkenyl substituted with 0-2 R^(1b), C₂₋₆alkynyl substituted with0-2 R^(1b), aryl substituted with 0-2 R^(1b), 5-10 membered heteroarylsubstituted with 0-2 R^(1b) and consisting of carbon atoms and 1-4heteroatoms selected from O, N, and S(O)₀₋₂, C₃₋₁₀ cycloalkylsubstituted with 0-2 R^(1b), and a 3-8 membered heterocycle substitutedwith 0-2 R^(1b) and consisting of carbon atoms and 1-3 heteroatomsselected from O, N, and S(O)₀₋₂;

R^(1b), at each occurrence, is selected from OH substituted with 0-1R^(1c), SH substituted with 0-1 R^(1c), S, O, halogen, methanesulfonyl,NH₂ substituted with 0-2 R^(1c), —CN, NO₂, C₁₋₆ alkyl substituted with0-3 R^(1c), C₂₋₆alkenyl substituted with 0-2 R^(1c), aryl substitutedwith 0-2 R^(1c), 5-10 membered heteroaryl substituted with 0-2 R^(1c)and consisting of carbon atoms and 1-4 heteroatoms selected from O, N,and S(O)₀₋₂, C₃₋₁₀ cycloalkyl substituted with 0-2 R^(1c), and a 3-8membered heterocycle substituted with 0-2 R^(1c) and consisting ofcarbon atoms and 1-3 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(1c), at each occurrence, is selected from OH substituted with 0-1R^(1d), SH substituted with 0-1 R^(1d), S, O, halogen, NH₂ substitutedwith 0-2 R^(1d), —CN, NO₂, C₁₋₆alkyl substituted with 0-2 R^(1d),C₂₋₆alkenyl substituted with 0-2 R^(1d), aryl substituted with 0-2R^(1d), 5-10 membered heteroaryl substituted with 0-2 R^(1d) andconsisting of carbon atoms and 1-4 heteroatoms selected from O, N, andS(O)₀₋₂, C₃₋₁₀ cycloalkyl substituted with 0-2 R^(1d), and a 3-8membered heterocycle substituted with 0-2 R^(1d) and consisting ofcarbon atoms and 1-3 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(1d), at each occurrence, is selected from OH, SH, S, O, halogen, NH₂,—CN, NO₂, C₁₋₆ alkyl, C₂₋₆alkenyl, aryl, CF₃, and OCF₃;

R² is selected from —C≡C—R^(2a), —CH═CH—R^(2a) substituted with 0-2R^(2a), aryl substituted with 0-3 R^(2a), and 5-10 membered heteroarylsubstituted with 0-3 R^(2a) and consisting of carbon atoms and 1-4heteroatoms selected from O, N, and S(O)₀₋₂;

R^(2a), at each occurrence, is selected from OH substituted with 0-1R^(2b), SH substituted with 0-1 R^(2b), S, O, halogen, NH₂ substitutedwith 0-2 R^(2b), —CN, NO₂, C₁₋₆ alkyl substituted with 0-2 R^(2b),C₂₋₆alkenyl substituted with 0-2 R^(2b), aryl substituted with 0-2R^(2b), 5-10 membered heteroaryl substituted with 0-2 R^(2b) andconsisting of carbon atoms and 1-4 heteroatoms selected from O, N, andS(O)₀₋₂, C₃₋₁₀ cycloalkyl substituted with 0-2 R^(2b), and a 3-8membered heterocycle substituted with 0-2 R^(2b) and consisting ofcarbon atoms and 1-3 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(2b), at each occurrence, is selected from OH substituted with 0-1R^(2c), SH substituted with 0-1 R^(2c), S, O substituted with 0-1R^(2c), halogen, methanesulfonyl, NH₂ substituted with 0-2 R^(2c), —CN,NO₂, C₁₋₆ alkyl substituted with 0-2 R^(2c), C₂₋₆alkenyl substitutedwith 0-2 R^(2c), aryl substituted with 0-2 R^(2c), 5-10 memberedheteroaryl substituted with 0-2 R^(2c) and consisting of carbon atomsand 1-4 heteroatoms selected from O, N, and S(O)₀₋₂, C₃₋₁₀ cycloalkylsubstituted with 0-2 R^(2c), and a 3-8 membered heterocycle substitutedwith 0-2 R^(2c) and consisting of carbon atoms and 1-3 heteroatomsselected from O, N, and S(O)₀₋₂;

R^(2c), at each occurrence, is selected from OH substituted with 0-1R^(2d), SH substituted with 0-1 R^(2d), S, O, halogen, NH₂ substitutedwith 0-2 R^(2d), —CN, NO₂, C₁₋₆alkyl substituted with 0-2 R^(2d),C₂₋₆alkenyl substituted with 0-2 R^(2d), aryl substituted with 0-2R^(2d), 5-10 membered heteroaryl substituted with 0-2 R^(2d) andconsisting of carbon atoms and 1-4 heteroatoms selected from O, N, andS(O)₀₋₂, C₃₋₁₀ cycloalkyl substituted with 0-2 R^(2d), and a 3-8membered heterocycle substituted with 0-2 R^(2d) and consisting ofcarbon atoms and 1-3 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(2d), at each occurrence, is selected from OH, SH, S, O, halogen, NH₂,—CN, NO₂, C₁₋₆ alkyl, C₂₋₆alkenyl, aryl, CF₃, and OCF₃;

R³ is selected from halogen and C₁₋₆ alkyl substituted with 0-2 R^(3a);

R^(3a), at each occurrence, is selected from OH, O, S, halogen, C(O)NH₂,C(O)NH—C₁₋₄ alkyl, and C(O)N(C₁₋₄ alkyl)₂;

alternatively, R³ and R^(5e) combine to form a 5, 6, or 7 membered ringconsisting of carbon atoms and 0-2 heteroatoms selected from O, N, andS(O)₀₋₂ and there are 0-2 ring double bonds in the bridging portionformed by R³ and R^(5e);

R^(4a), at each occurrence, is selected from H, halogen, and C₁₋₆ alkylsubstituted with 0-2 R^(4d);

R^(4d), at each occurrence, is selected from OH, O, halogen, NH₂,NH—C₁₋₄ alkyl, and N(C₁₋₄ alkyl)₂;

R^(4b), at each occurrence, is selected from H, halogen, and C₁₋₆alkylsubstituted with 0-2 R^(4e)

R^(4e), at each occurrence, is selected from OH, O, halogen, NH₂,NH—C₁₋₄alkyl, and N(C₁₋₄ alkyl)₂;

R^(4c), at each occurrence, is selected from H, halogen, and C₁₋₆alkylsubstituted with 0-2 R^(4f);

R^(4f), at each occurrence, is selected from OH, O, halogen, NH₂,NH—C₁₋₄ alkyl, and N(C₁₋₄ alkyl)₂;

R^(5a), at each occurrence, is selected from H, halogen, CH₃, and CH₂CH₃;

R^(5b), at each occurrence, is selected from H, halogen, CH₃, and CH₂CH₃;

R^(5c), at each occurrence, is selected from H, halogen, CH₃, and CH₂CH₃;

R^(5d), at each occurrence, is selected from H, halogen, CH₃, and CH₂CH₃; and,

R^(5e), at each occurrence, is selected from H, halogen, CH₃, and CH₂CH₃.

In another embodiment, the present invention provides a novel compoundof formula I or a pharmaceutically acceptable salt thereof, wherein:

X is selected from O, S, OCH₂, and SCH₂;

X¹ is O or S;

R¹ is selected from H, C₁₋₈ alkyl, C₂₋₈ alkenyl, aryl, 5-10 memberedheteroaryl consisting of carbon atoms and 1-4 heteroatoms selected fromO, N, and S(O)₀₋₂, C₃₋₁₀ cycloalkyl, and a 3-8 membered heterocycleconsisting of carbon atoms and 1-3 heteroatoms selected from O, N, andS(O)₀₋₂, wherein each R¹ group is substituted with 0-4 R^(1a);

R^(1a), at each occurrence, is selected from OH substituted with 0-1R^(1b), SH substituted with 0-1 R^(1b), S, O, halogen, NH₂ substitutedwith 0-2 R^(1b), —CN, NO₂, C₁₋₆alkyl substituted with 0-2 R^(1b),C₂₋₆alkenyl substituted with 0-2 R^(1b), C₂₋₆alkynyl substituted with0-2 R^(1b), aryl substituted with 0-2 R^(1b), 5-10 membered heteroarylsubstituted with 0-2 R^(1b) and consisting of carbon atoms and 1-4heteroatoms selected from O, N, and S(O)₀₋₂, C₃₋₁₀ cycloalkylsubstituted with 0-2 R^(1b), and a 3-8 membered heterocycle substitutedwith 0-2 R^(1b) and consisting of carbon atoms and 1-3 heteroatomsselected from O, N, and S(O)₀₋₂;

R^(1b), at each occurrence, is selected from OH substituted with 0-1R^(1c), SH substituted with 0-1 R^(1c), S, O, halogen, NH₂ substitutedwith 0-2 R^(1c), —CN, NO₂, C₁₋₆alkyl substituted with 0-2 R^(1c),C₂₋₆alkenyl substituted with 0-2 R^(1c), aryl substituted with 0-2R^(1c), 5-10 membered heteroaryl substituted with 0-2 R^(1c) andconsisting of carbon atoms and 1-4 heteroatoms selected from O, N, andS(O)₀₋₂, C₃₋₁₀ cycloalkyl substituted with 0-2 R^(1c), and a 3-8membered heterocycle substituted with 0-2 R^(1c) and consisting ofcarbon atoms and 1-3 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(1c), at each occurrence, is selected from OH substituted with 0-1R^(1d), SH substituted with 0-1 R^(1d), S, O, halogen, NH₂ substitutedwith 0-2 R^(1d), —CN, NO₂, C₁₋₆alkyl substituted with 0-2 R^(1d),C₂₋₆alkenyl substituted with 0-2 R^(1d), aryl substituted with 0-2R^(1d), 5-10 membered heteroaryl substituted with 0-2 R^(1d) andconsisting of carbon atoms and 1-4 heteroatoms selected from O, N, andS(O)₀₋₂, C₃₋₁₀ cycloalkyl substituted with 0-2 R^(1d), and a 3-8membered heterocycle substituted with 0-2 R^(1d) and consisting ofcarbon atoms and 1-3 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(1d), at each occurrence, is selected from OH, SH, S, O, halogen, NH₂,—CN, NO₂, C₁₋₆ alkyl, C₂₋₆alkenyl, aryl, CF₃, and OCF₃;

R² is selected from —C≡C—R^(2a), —CH═CH—R^(2a) substituted with 0-2R^(2a), aryl substituted with 0-3 R^(2a), and 5-10 membered heteroarylsubstituted with 0-3 R^(2a) and consisting of carbon atoms and 1-4heteroatoms selected from O, N, and S(O)₀₋₂;

R^(2a), at each occurrence, is selected from OH substituted with 0-1R^(2b), SH substituted with 0-1 R^(2b), S, O, halogen, NH₂ substitutedwith 0-2 R^(2b), —CN, NO₂, C₁₋₆alkyl substituted with 0-2 R^(2b),C₂₋₆alkenyl substituted with 0-2 R^(2b), aryl substituted with 0-2R^(2b), 5-10 membered heteroaryl substituted with 0-2 R^(2b) andconsisting of carbon atoms and 1-4 heteroatoms selected from O, N, andS(O)₀₋₂, C₃₋₁₀ cycloalkyl substituted with 0-2 R^(2b), and a 3-8membered heterocycle substituted with 0-2 R^(2b) and consisting ofcarbon atoms and 1-3 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(2b), at each occurrence, is selected from OH substituted with 0-1R^(2c), SH substituted with 0-1 R^(2c), S, O, halogen, NH₂ substitutedwith 0-2 R^(2c), —CN, NO₂, C₁₋₆ alkyl substituted with 0-2 R^(2c),C₂₋₆alkenyl substituted with 0-2 R^(2c), aryl substituted with 0-2R^(2c), 5-10 membered heteroaryl substituted with 0-2 R^(2c) andconsisting of carbon atoms and 1-4 heteroatoms selected from O, N, andS(O)₀₋₂, C₃₋₁₀ cycloalkyl substituted with 0-2 R^(2c), and a 3-8membered heterocycle substituted with 0-2 R^(2c) and consisting ofcarbon atoms and 1-3 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(2c), at each occurrence, is selected from OH substituted with 0-1R^(2d), SH substituted with 0-1 R^(2d), S, O, halogen, NH₂ substitutedwith 0-2 R^(2d), —CN, NO₂, C₁₋₆ alkyl substituted with 0-2 R^(2d),C₂₋₆alkenyl substituted with 0-2 R^(2d), aryl substituted with 0-2R^(2d), 5-10 membered heteroaryl substituted with 0-2 R^(2d) andconsisting of carbon atoms and 1-4 heteroatoms selected from O, N, andS(O)₀₋₂, C₃₋₁₀ cycloalkyl substituted with 0-2 R^(2d), and a 3-8membered heterocycle substituted with 0-2 R^(2d) and consisting ofcarbon atoms and 1-3 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(2d), at each occurrence, is selected from OH, SH, S, O, halogen, NH₂,—CN, NO₂, C₁₋₆ alkyl, C₂₋₆alkenyl, aryl, CF₃, and OCF₃;

R³ is selected from halogen and C₁₋₆ alkyl substituted with 0-2 R^(3a);

R^(3a), at each occurrence, is selected from OH, O, S, halogen, C(O)NH₂,C(O)NH—C₁₋₄ alkyl, and C(O)N(C₁₋₄ alkyl)₂;

alternatively, R³ and R^(5e) combine to form a 5, 6, or 7 membered ringconsisting of carbon atoms and 0-2 heteroatoms selected from O, N, andS(O)₀₋₂ and there are 0-2 ring double bonds in the bridging portionformed by R³ and R^(5e);

R^(4a), at each occurrence, is selected from H, halogen, and C₁₋₆ alkylsubstituted with 0-2 R^(4d)

R^(4d), at each occurrence, is selected from OH, O, halogen, NH₂,NH—C₁₋₄ alkyl, and N(C₁₋₄alkyl)₂;

R^(4b), at each occurrence, is selected from H, halogen, and C₁₋₆alkylsubstituted with 0-2 R^(4e)

R^(4e), at each occurrence, is selected from OH, O, halogen, NH₂,NH—C₁₋₄alkyl, and N(C₁₋₄ alkyl)₂;

R^(4c), at each occurrence, is selected from H, halogen, and C₁₋₆alkylsubstituted with 0-2 R^(4f);

R^(4f), at each occurrence, is selected from OH, O, halogen, NH₂,NH—C₁₋₄ alkyl, and N(C₁₋₄ alkyl)₂;

R^(5a), at each occurrence, is selected from H, halogen, CH₃, and CH₂CH₃;

R^(5b), at each occurrence, is selected from H, halogen, CH₃, and CH₂CH₃;

R^(5c), at each occurrence, is selected from H, halogen, CH₃, and CH₂CH₃;

R^(5d), at each occurrence, is selected from H, halogen, CH₃, and CH₂CH₃; and,

R^(5e), at each occurrence, is selected from H, halogen, CH₃, and CH₂CH₃.

In a embodiment, the present invention provides a novel compound offormula Ia:

or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a novel compoundof formula II:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, C₁₋₈ alkyl, heteroaryl, and C₃₋₁₀ cycloalkyl, wherein each R¹group is substituted with 0-4 R^(1a);

R^(1a), at each occurrence, is selected from C₁₋₆ alkyl substituted with0-3 R^(1b); C₂₋₆alkynyl substituted with 0-2 R^(1b); aryl substitutedwith 0-2 R^(1b), heteroaryl substituted with 0-2 R^(1b), C₃₋₁₀cycloalkyl substituted with 0-2 R^(1b), and a heterocycle substitutedwith 0-2 R^(1b);

R^(1b), at each occurrence, is selected from OH substituted with 0-1R^(1c), SH substituted with 0-1 R^(1c), Cl, F, NH₂ substituted with 0-2R^(1c), —CN, NO₂, methanesulfonyl, C₁₋₄ alkyl substituted with 0-3R^(1c), C₂₋₄alkenyl substituted with 0-2 R^(1c), aryl substituted with0-2 R^(1c), heteroaryl substituted with 0-2 R^(1c), C₃₋₆cycloalkylsubstituted with 0-2 R^(1c), and a heterocycle substituted with 0-2R^(1c)

R^(1c), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, and C₂₋₄alkenyl, aryl substituted with 0-2 R^(1d),heteroaryl substituted with 0-2 R^(1d) and, C₃₋₆cycloalkyl substitutedwith 0-2 R^(1d), and a heterocycle substituted with 0-2 R^(1d);

R^(1d), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, and C₂₋₄ alkenyl;

R^(2a) is selected from C₁₋₆ alkyl substituted with 0-2 R^(2b), arylsubstituted with 0-2 R^(2b), and heteroaryl substituted with 0-2 R^(2b);

R^(2b), at each occurrence, is selected from OH substituted with 0-1R^(2c), SH substituted with 0-1 R^(2c), Cl, F, NH₂ substituted with 0-2R^(2c), —CN, NO₂, methanesulfonyl, C₁₋₄ alkyl substituted with 0-2R^(2c), C₂₋₄alkenyl substituted with 0-2 R^(2c), aryl substituted with0-2 R^(2c), heteroaryl substituted with 0-2 R^(2c), C₃₋₆cycloalkylsubstituted with 0-2 R^(2c), and a heterocycle substituted with 0-2R^(2c)

R^(2c), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄alkyl, C₂₋₄ alkenyl, aryl substituted with 0-2 R^(2d), andheteroaryl substituted with 0-2 R^(2d);

R^(2d), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, and C₂₋₄ alkenyl;

R³ is selected from Cl, F, CH₃, and CH₂ CH₃;

alternatively, R³ and R^(5e) combine to form a 5, 6, or 7 membered ringconsisting of carbon atoms and 0-2 heteroatoms selected from O, N, andS(O)₀₋₂ and there are 0-2 ring double bonds in the bridging portionformed by R³ and R^(5e);

R^(4a), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(4b), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(4c), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(5a), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(5b), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(5c), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(5d), at each occurrence, is selected from H, Cl, F, and CH₃; and,

R^(5e), at each occurrence, is selected from H, Cl, F, and CH₃.

In another embodiment, the present invention provides a novel compoundof formula II or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, C₁₋₈ alkyl, 5-10 membered heteroaryl consisting of carbon atomsand 1-4 heteroatoms selected from O, N, and S(O)₀₋₂, and C₃₋₁₀cycloalkyl, wherein each R¹ group is substituted with 0-4 R^(1a);

R^(1a), at each occurrence, is selected from C₁₋₆ alkyl substituted with0-3 R^(1b); C₂₋₆ alkynyl substituted with 0-2 R^(1b); aryl substitutedwith 0-2 R^(1b), 5-10 membered heteroaryl substituted with 0-2 R^(1b)and consisting of carbon atoms and 1-4 heteroatoms selected from O, N,and S(O)₀₋₂, C₃₋₁₀ cycloalkyl substituted with 0-2 R^(1b), and a 3-8membered heterocycle substituted with 0-2 R^(1b) and consisting ofcarbon atoms and 1-2 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(1b), at each occurrence, is selected from OH substituted with 0-1R^(1c), SH substituted with 0-1 R^(1c), Cl, F, NH₂ substituted with 0-2R^(1c), —CN, NO₂, methanesulfonyl, C₁₋₄ alkyl substituted with 0-3R^(1c), C₂₋₄alkenyl substituted with 0-2 R^(1c), aryl substituted with0-2 R^(1c), 5-10 membered heteroaryl substituted with 0-2 R^(1c) andconsisting of carbon atoms and 1-4 heteroatoms selected from O, N, andS(O)₀₋₂, C₃₋₆cycloalkyl substituted with 0-2 R^(1c), and a 3-6 memberedheterocycle substituted with 0-2 R^(1c) and consisting of carbon atomsand 1-2 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(1c), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, and C₂₋₄alkenyl, aryl substituted with 0-2 R^(1d), 5-10membered heteroaryl substituted with 0-2 R^(1d) and consisting of carbonatoms and 1-4 heteroatoms selected from O, N, and S(O)₀₋₂, C₃₋₆cycloalkyl substituted with 0-2 R^(1d), and a 3-6 membered heterocyclesubstituted with 0-2 R^(1d) and consisting of carbon atoms and 1-2heteroatoms selected from O, N, and S(O)₀₋₂;

R^(1d), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, and C₂₋₄alkenyl;

R^(2a) is selected from C₁₋₆alkyl substituted with 0-2 R^(2b), arylsubstituted with 0-2 R^(2b), and 5-10 membered heteroaryl substitutedwith 0-2 R^(2b) and consisting of carbon atoms and 1-4 heteroatomsselected from O, N, and S(O)₀₋₂;

R^(2b), at each occurrence, is selected from OH substituted with 0-1R^(2c), SH substituted with 0-1 R^(2c), Cl, F, NH₂ substituted with 0-2R^(2c), —CN, NO₂, methanesulfonyl, C₁₋₄alkyl substituted with 0-2R^(2c), C₂₋₄alkenyl substituted with 0-2 R^(2c), aryl substituted with0-2 R^(2c), 5-10 membered heteroaryl substituted with 0-2 R^(2c) andconsisting of carbon atoms and 1-4 heteroatoms selected from O, N, andS(O)₀₋₂, C₃₋₆cycloalkyl substituted with 0-2 R^(2c), and a 3-6 memberedheterocycle substituted with 0-2 R^(2c) and consisting of carbon atomsand 1-2 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(2c), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄alkyl, C₂₋₄ alkenyl, aryl substituted with 0-2 R^(2d), and 5-10membered heteroaryl substituted with 0-2 R^(2d) and consisting of carbonatoms and 1-4 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(2d), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, and C₂₋₄ alkenyl;

R³ is selected from Cl, F, CH₃, and CH₂ CH₃;

alternatively, R³ and R^(5e) combine to form a 5, 6, or 7 membered ringconsisting of carbon atoms and 0-2 heteroatoms selected from O, N, andS(O)₀₋₂ and there are 0-2 ring double bonds in the bridging portionformed by R³ and R^(5e);

R^(4a), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(4b), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(4c), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(5a), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(5b), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(5c), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(5d), at each occurrence, is selected from H, Cl, F, and CH₃; and,

R^(5e), at each occurrence, is selected from H, Cl, F, and CH₃.

In another embodiment, the present invention provides a novel compoundof formula II or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H or C₁₋₄ alkyl substituted with 1-4 R^(1a);

R^(1a), at each occurrence, is selected from aryl substituted with 0-2R^(1b), 5-10 membered heteroaryl substituted with 0-2 R^(1b) andconsisting of carbon atoms and 1-4 heteroatoms selected from O, N, andS(O)₀₋₂, C₃₋₁₀ cycloalkyl substituted with 0-2 R^(1b), and a 3-8membered heterocycle substituted with 0-2 R^(1b) and consisting ofcarbon atoms and 1-2 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(1b), at each occurrence, is selected from OH substituted with 0-1R^(1c), SH substituted with 0-1 R^(1c), Cl, F, NH₂ substituted with 0-2R^(1c), —CN, NO₂, C₁₋₄ alkyl substituted with 0-2 R^(1c), C₂₋₄ alkenylsubstituted with 0-2 R^(1c), aryl substituted with 0-2 R^(1c), 5-10membered heteroaryl substituted with 0-2 R^(1c) and consisting of carbonatoms and 1-4 heteroatoms selected from O, N, and S(O)₀₋₂,C₃₋₆cycloalkyl substituted with 0-2 R^(1c), and a 3-6 memberedheterocycle substituted with 0-2 R^(1c) and consisting of carbon atomsand 1-2 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(1c), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, and C₂₋₄alkenyl, aryl substituted with 0-2 R^(1d), 5-10membered heteroaryl substituted with 0-2 R^(1d) and consisting of carbonatoms and 1-4 heteroatoms selected from O, N, and S(O)₀₋₂, C₃₋₆cycloalkyl substituted with 0-2 R^(1d), and a 3-6 membered heterocyclesubstituted with 0-2 R^(1d) and consisting of carbon atoms and 1-2heteroatoms selected from O, N, and S(O)₀₋₂;

R^(1d), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, and C₂₋₄alkenyl;

R^(2a) is selected from C₁₋₆ alkyl substituted with 0-2 R^(2b), arylsubstituted with 0-2 R^(2b), and 5-10 membered heteroaryl substitutedwith 0-2 R^(2b) and consisting of carbon atoms and 1-4 heteroatomsselected from O, N, and S(O)₀₋₂;

R^(2b), at each occurrence, is selected from OH substituted with 0-1R^(2c), SH substituted with 0-1 R^(2c), Cl, F, NH₂ substituted with 0-2R^(2c), —CN, NO₂, C₁₋₄ alkyl substituted with 0-2 R^(2c), C₂₋₄alkenylsubstituted with 0-2 R^(2c), aryl substituted with 0-2 R^(2c), 5-10membered heteroaryl substituted with 0-2 R^(2c) and consisting of carbonatoms and 1-4 heteroatoms selected from O, N, and S(O)₀₋₂,C₃₋₆cycloalkyl substituted with 0-2 R^(2c), and a 3-6 memberedheterocycle substituted with 0-2 R^(2e) and consisting of carbon atomsand 1-2 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(2c), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, C₂₋₄ alkenyl, aryl substituted with 0-2 R^(2d), and5-10 membered heteroaryl substituted with 0-2 R^(2d) and consisting ofcarbon atoms and 1-4 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(2d), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, and C₂₋₄ alkenyl;

R³ is selected from Cl, F, CH₃, and CH₂ CH₃;

alternatively, R³ and R^(5e) combine to form a 5, 6, or 7 membered ringconsisting of carbon atoms and 0-2 heteroatoms selected from O, N, andS(O)₀₋₂ and there are 0-2 ring double bonds in the bridging portionformed by R³ and R^(5e);

R^(4a), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(4b), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(4c), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(5a), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(5b), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(5c), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(5d), at each occurrence, is selected from H, Cl, F, and CH₃; and,

R^(5e), at each occurrence, is selected from H, Cl, F, and CH₃.

In another embodiment, the present invention provides a novel compoundof formula IIa:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, C₁₋₆ alkyl, aryl, heteroaryl, and C₃₋₁₀ cycloalkyl, whereineach R¹ group is substituted with 0-1 R^(1a);

R^(1a), at each occurrence, is selected from C₁₋₆ alkyl substituted with0-3 R^(1b); C₂₋₆alkynyl substituted with 0-2 R^(1b); aryl substitutedwith 0-2 R^(1b), heteroaryl substituted with 0-2 R^(1b) and,C₅₋₆cycloalkyl substituted with 0-2 R^(1b), and a heterocyclesubstituted with 0-2 R^(1b) and;

R^(1b), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, methanesulfonyl, C₁₋₄alkyl substituted with 0-3 R^(1c), C₂₋₄alkenylsubstituted with 0-2 R^(1c), aryl substituted with 0-2 R^(1c),heteroaryl substituted with 0-2 R^(1c), C₅₋₆cycloalkyl substituted with0-2 R^(1c), and a heterocycle substituted with 0-2 R^(1c);

R^(1c), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, and C₂₋₄alkenyl, aryl substituted with 0-2 R^(1d),heteroaryl substituted with 0-2 R^(1d), C₅₋₆cycloalkyl substituted with0-2 R^(1d), and a heterocycle substituted with 0-2 R^(1d);

R^(1d), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, and C₂₋₄ alkenyl;

R^(2a) is selected from C₁₋₆ alkyl substituted with 0-2 R^(2b), arylsubstituted with 0-2 R^(2b), and heteroaryl substituted with 0-2 R^(2b);

R^(2b), at each occurrence, is selected from OH substituted with 0-1R^(2c), SH, Cl, F, NH₂, —CN, NO₂, methanesulfonyl, C₁₋₄ alkyl,C₂₋₄alkenyl, aryl, heteroaryl, C₅₋₆cycloalkyl, and a heterocycle;

R^(2c), at each occurrence, is C₁₋₄ alkyl;

R³ is selected from Cl, F, CH₃, and CH₂ CH₃; and,

alternatively, R³ and R^(5e) combine to form a 5, 6, or 7 membered ringconsisting of carbon atoms and 0-2 heteroatoms selected from O, N, andS(O)₀₋₂ and there are 0-2 ring double bonds in the bridging portionformed by R³ and R^(5e).

In another embodiment, the present invention provides a novel compoundof formula IIa or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, C₁₋₆ alkyl, aryl, 5-6 membered heteroaryl consisting of carbonatoms and 1-4 heteroatoms selected from O, N, and S(O)₀₋₂, and C₃₋₁₀cycloalkyl, wherein each R¹ group is substituted with 0-1 R^(1a);

R^(1a), at each occurrence, is selected from C₁₋₆ alkyl substituted with0-3 R^(1b); C₂₋₆alkynyl substituted with 0-2 R^(1b); aryl substitutedwith 0-2 R^(1b), 5-6 membered heteroaryl substituted with 0-2 R^(1b) andconsisting of carbon atoms and 1-2 heteroatoms selected from O, N, andS(O)₀₋₂, C₅₋₆ cycloalkyl substituted with 0-2 R^(1b), and a 5-6 memberedheterocycle substituted with 0-2 R^(1b) and consisting of carbon atomsand 1-2 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(1b), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, methanesulfonyl, C₁₋₄ alkyl substituted with 0-3 R^(1c),C₂₋₄alkenyl substituted with 0-2 R^(1c), aryl substituted with 0-2R^(1c), 5-6 membered heteroaryl substituted with 0-2 R^(1c) andconsisting of carbon atoms and 1-2 heteroatoms selected from O, N, andS(O)₀₋₂, C₅₋₆cycloalkyl substituted with 0-2 R^(1c), and a 5-6 memberedheterocycle substituted with 0-2 R^(1c) and consisting of carbon atomsand 1-2 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(1c), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, and C₂₋₄alkenyl, aryl substituted with 0-2 R^(1d), 5-6membered heteroaryl substituted with 0-2 R^(1d) and consisting of carbonatoms and 1-2 heteroatoms selected from O, N, and S(O)₀₋₂,C₅₋₆cycloalkyl substituted with 0-2 R^(1d), and a 5-6 memberedheterocycle substituted with 0-2 R^(1d) and consisting of carbon atomsand 1-2 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(1d), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, and C₂₋₄ alkenyl;

R^(2a) is selected from C₁₋₆alkyl substituted with 0-2 R^(2b), arylsubstituted with 0-2 R^(2b), and 5-6 membered heteroaryl substitutedwith 0-2 R^(2b) and consisting of carbon atoms and 1-2 heteroatomsselected from O, N, and S(O)₀₋₂;

R^(2b), at each occurrence, is selected from OH substituted with 0-1R^(2c), SH, Cl, F, NH₂, —CN, NO₂, methanesulfonyl, C₁₋₄ alkyl, C₂₋₄alkenyl, aryl, 5-6 membered heteroaryl consisting of carbon atoms and1-2 heteroatoms selected from O, N, and S(O)₀₋₂, C₅₋₆cycloalkyl, and a5-6 membered heterocycle and consisting of carbon atoms and 1-2heteroatoms selected from O, N, and S(O)₀₋₂;

R^(2c), at each occurrence, is C₁₋₄ alkyl;

R³ is selected from Cl, F, CH₃, and CH₂ CH₃; and,

alternatively, R³ and R^(5e) combine to form a 5, 6, or 7 membered ringconsisting of carbon atoms and 0-2 heteroatoms selected from O, N, andS(O)₀₋₂ and there are 0-2 ring double bonds in the bridging portionformed by R³ and R^(5e).

In another embodiment, the present invention provides a novel compoundof formula IIa or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H or C₁₋₄alkyl substituted with 1 R^(1a;)

R^(1a), at each occurrence, is selected from aryl substituted with 0-2R^(1b), 5-6 membered heteroaryl substituted with 0-2 R^(1b) andconsisting of carbon atoms and 1-2 heteroatoms selected from O, N, andS(O)₀₋₂, C₅₋₆cycloalkyl substituted with 0-2 R^(1b), and a 5-6 memberedheterocycle substituted with 0-2 R^(1b) and consisting of carbon atomsand 1-2 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(1b), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl substituted with 0-2 R^(1c), C₂₋₄ alkenyl substitutedwith 0-2 R^(1c), aryl substituted with 0-2 R^(1c), 5-6 memberedheteroaryl substituted with 0-2 R^(1c) and consisting of carbon atomsand 1-2 heteroatoms selected from O, N, and S(O)₀₋₂, C₅₋₆cycloalkylsubstituted with 0-2 R^(1c), and a 5-6 membered heterocycle substitutedwith 0-2 R^(1c) and consisting of carbon atoms and 1-2 heteroatomsselected from O, N, and S(O)₀₋₂;

R^(1c), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, and C₂₋₄alkenyl, aryl substituted with 0-2 R^(1d), 5-6membered heteroaryl substituted with 0-2 R^(1d) and consisting of carbonatoms and 1-2 heteroatoms selected from O, N, and S(O)₀₋₂,C₅₋₆cycloalkyl substituted with 0-2 R^(1d), and a 5-6 memberedheterocycle substituted with 0-2 R^(1d) and consisting of carbon atomsand 1-2 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(1d), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, and C₂₋₄ alkenyl;

R^(2a) is selected from C₁₋₆alkyl substituted with 0-2 R^(2b), arylsubstituted with 0-2 R^(2b), and 5-6 membered heteroaryl substitutedwith 0-2 R^(2b) and consisting of carbon atoms and 1-2 heteroatomsselected from O, N, and S(O)₀₋₂;

R^(2b), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, C₂₋₄ alkenyl, aryl, 5-6 membered heteroaryl consistingof carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)₀₋₂,C₅₋₆cycloalkyl, and a 5-6 membered heterocycle and consisting of carbonatoms and 1-2 heteroatoms selected from O, N, and S(O)₀₋₂;

R³ is selected from Cl, F, CH₃, and CH₂ CH₃; and,

alternatively, R³ and R^(5e) combine to form a 5, 6, or 7 membered ringconsisting of carbon atoms and 0-2 heteroatoms selected from O, N, andS(O)₀₋₂ and there are 0-2 ring double bonds in the bridging portionformed by R³ and R^(5e).

In another embodiment, the present invention provides a novel compoundof formula IIa or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, C₁₋₆ alkyl, aryl, heteroaryl, C₃₋₁₀ cycloalkyl, wherein each R¹group is substituted with 0-1 R^(1a);

R^(1a), at each occurrence, is selected from C₁₋₄ alkyl substituted with0-3 R^(1b); C₂₋₆alkynyl substituted with 0-1 R^(1b), aryl substitutedwith 0-1 R^(1b), heteroaryl substituted with 0-1 R^(1b), C₅₋₆ cycloalkylsubstituted with 0-1 R^(1b), and a heterocycle substituted with 0-1R^(1b);

R^(1b), at each occurrence, is selected from Cl, F, methanesulfonyl, andC₁₋₄ alkyl substituted with 0-3 R^(1c), and;

R^(1c), at each occurrence, is selected from Cl, F and a heterocycle;

R^(2a) is selected from C₁₋₆ alkyl substituted with 0-2 R^(2b), arylsubstituted with 0-2 R^(2b), and heteroaryl substituted with 0-2 R^(2b);

R^(2b), at each occurrence, is selected from OH optionally substitutedwith C₁₋₄ alkyl, Cl, F, methanesulfonyl, aryl, heteroaryl,C₅₋₆cycloalkyl, and a heterocycle;

R³ is selected from Cl, F, CH₃, and CH₂ CH₃.

In another embodiment, the present invention provides a novel compoundof formula IIa or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, C₁₋₆alkyl, aryl, 5-6 membered heteroaryl consisting of carbonatoms and 1-2 heteroatoms selected from O and N; C₃₋₁₀ cycloalkyl,wherein each R¹ group is substituted with 0-1 R^(1a);

R^(1a), at each occurrence, is selected from C₁₋₄alkyl substituted with0-3 R^(1b); C₂₋₆alkynyl substituted with 0-1 R^(1b) aryl substitutedwith 0-1 R^(1b), 5-6 membered heteroaryl substituted with 0-1 R^(1b) andconsisting of carbon atoms and 1-2 heteroatoms selected from O and N,C₅₋₆ cycloalkyl substituted with 0-1 R^(1b), and a 5-6 memberedheterocycle substituted with 0-1 R^(1b);

R^(1b), at each occurrence, is selected from Cl, F, methanesulfonyl, andC₁₋₄alkyl substituted with 0-3 R^(1c), and;

R^(1c), at each occurrence, is selected from Cl, F and a 5-6 memberedheterocycle consisting of carbon atoms and 1-2 heteroatoms selected fromO and N;

R^(2a) is selected from C₁₋₆alkyl substituted with 0-2 R^(2b), arylsubstituted with 0-2 R^(2b), and 5-6 membered heteroaryl substitutedwith 0-2 R^(2b) and consisting of carbon atoms and 1-2 heteroatomsselected from O and N;

R^(2b), at each occurrence, is selected from OH optionally substitutedwith C₁₋₄ alkyl, Cl, F, methanesulfonyl, aryl, 5-6 membered heteroarylconsisting of carbon atoms and 1-2 heteroatoms selected from O and N,C₅₋₆cycloalkyl, and a 5-6 membered heterocycle consisting of carbonatoms and 1-2 heteroatoms selected from O and N;

R³ is selected from Cl, F, CH₃, and CH₂ CH₃.

In another embodiment, the present invention provides a novel compoundof formula IIb

or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a novel compoundof formula IIb, wherein R¹ is C₁₋₆ alkyl.

In another embodiment, the present invention provides a novel compoundof formula IIb, wherein R^(2a) is C₁₋₄ alkyl substituted with aheterocycle.

In another embodiment, the present invention provides a novel compoundof formula IIb, wherein R^(2a) is C₁₋₄ alkyl substituted withmorpholinyl.

In another embodiment, the present invention provides a novel compoundof formula IIb, wherein R³ is selected from Cl and CH₃.

In another embodiment, the present invention provides a novel compoundof formula IIb, wherein X is selected from S and SCH₂

In another embodiment, the present invention provides a novel compoundof formula IIb, wherein X is S.

In another embodiment, the present invention provides a novel compoundof formula IIb, wherein X is SCH₂.

In another embodiment, the present invention provides a novel compoundof formula IIb, wherein X¹ is O.

In another embodiment, the present invention provides a novel compoundof formula IIb, wherein X¹ is S.

In another embodiment, the present invention provides a novel compoundof formula IIb, wherein: R¹ is aryl substituted with 0-1 R^(1a); whereinR^(1a), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl.

In another embodiment, the present invention provides a novel compoundof formula IIb, wherein R¹ is C₁₋₆ alkyl substituted with R^(1a); andwherein R^(1a) is aryl substituted with 0-1 R^(1b); and wherein R^(1b)is selected from OH, SH, Cl, F, NH₂, —CN, NO₂, C₁₋₄ alkyl.

In another embodiment, the present invention provides a novel compoundof formula IIb, wherein: R¹ is C₁₋₆ alkyl substituted with R^(1a),wherein R^(1a) is heteroaryl substituted with 0-1 R^(1b); and whereinR^(1b) is selected from OH, SH, Cl, F, NH₂, —CN, NO₂, C₁₋₄alkyl.

In another embodiment, the present invention provides a novel compoundof formula IIb, wherein: R¹ is C₁₋₆ alkyl substituted with R^(1a),wherein R^(1a) is heterocyclyl substituted with 0-1 R^(1b); and whereinR^(1b) is selected from OH, SH, Cl, F, NH₂, —CN, NO₂, C₁₋₄alkyl.

In another embodiment, the present invention provides a novel compoundof formula IIb, wherein: R¹ is C₁₋₆ alkyl substituted with R^(1a),wherein R^(1a) is C₅₋₆cycloalkyl substituted with 0-2 R^(1b); andwherein R^(1b) is selected from OH, SH, Cl, F, NH₂, —CN, NO₂, C₁₋₄alkyl.

In another embodiment, the present invention provides a novel compoundof formula IIb, wherein: R^(2a) is aryl substituted with R^(2b); whereinR^(2b) is selected from OH, SH, Cl, F, NH₂, —CN, NO₂, C₁₋₄ alkyl.

In another embodiment, the present invention provides a novel compoundof formula IIb, wherein: R^(2a) is C₁₋₆ alkyl substituted with R^(2b);wherein R^(2b) is selected from aryl substituted with R^(2c); andwherein R^(2c) is selected from OH, SH, Cl, F, NH₂, —CN, NO₂, C₁₋₄alkyl.

In another embodiment, the present invention provides a novel compoundof formula IIb, wherein: R^(2a) is C₁₋₆ alkyl substituted with R^(2b);wherein R^(2b) is selected from heteroaryl substituted with R^(2c); andwherein R^(2c) is selected from OH, SH, Cl, F, NH₂, —CN, NO₂, C₁₋₄alkyl.

In another embodiment, the present invention provides a novel compoundselected from:

-   {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(3-piperidin-1-yl-propoxy)-phenylsulfanyl]-phenoxy}-acetic    acid;-   {2-Methyl-4-[3-(3-morpholin-4-yl-propoxy)-5-phenylethynyl-phenylsulfanyl]-phenoxy}-acetic    acid;-   {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(3-morpholin-4-yl-propoxy)-phenylsulfanyl]-phenoxy}-acetic    acid;-   {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(4-morpholin-4-ylmethyl-benzyloxy)-phenylsulfanyl]-phenoxy}-acetic    acid;-   {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(1-methyl-piperidin-4-ylmethoxy)-phenylsulfanyl]-phenoxy}-acetic    acid;-   {2-Methyl-4-[3-(3-morpholin-4-yl-propoxy)-5-(3-phenyl-prop-1-ynyl)-phenylsulfanyl]-phenoxy}-acetic    acid;-   {4-[3-(4-Fluoro-benzyloxy)-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   {4-[3-Cyclohexylmethoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   {4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   {4-[3-(4-Chloro-benzyloxy)-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-hydroxy-phenylsulfanyl]-phenoxy}-acetic    acid;-   {4-[3-But-2-ynyloxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   {2-Methyl-4-[3-(2-morpholin-4-yl-ethoxy)-5-phenylethynyl-phenylsulfanyl]-phenoxy}-acetic    acid;-   {2-Chloro-4-[3-(3-methoxy-prop-1-ynyl)-5-(3-morpholin-4-yl-propoxy)-phenyl-sulfanyl]-phenoxy}-acetic    acid;-   {2-Chloro-4-[3-(3-morpholin-4-yl-propoxy)-5-pent-1-ynyl-phenylsulfanyl]-phenoxy}-acetic    acid;-   {2-Methyl-4-[3-(3-morpholin-4-yl-propoxy)-5-(3-phenyl-prop-1-ynyl)-benzylsulfanyl]-phenoxy}-acetic    acid;-   {4-[3-(4-Fluoro-benzyloxy)-5-(3-morpholin-4-yl-prop-1    ynyl)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid; and,-   {2-Methyl-4-[3-(3-morpholin-4-yl-ethoxy)-5-(3-phenyl-prop-1-ynyl)-benzylsulfanyl]-phenoxy}-acetic    acid;

or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a novel compoundselected from:

-   {4-[3-Cyclohexylmethoxy-5-(4-methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   {4-[3-Cyclopentylmethoxy-5-(4-methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   {4-[3-Isobutoxy-5-(4-methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-methanesulfonyl-phenylethynyl)-phenyl-sulfanyl]-2-methyl-phenoxy}-acetic    acid;-   {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenyl-sulfanyl]-2-methyl-phenoxy}-acetic    acid;-   {4-[3-(2-Ethyl-butoxy)-5-phenylethynyl-phenylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   [4-(3-Cyclopentyloxy-5-phenylethynyl-phenylsulfanyl)-2-methyl-phenoxy]-acetic    acid;-   {4-[3-(4-Fluoro-phenylethynyl)-5-(4-methanesulfonyl-benzyloxy)-phenylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   [4-(3-Cyclopentylmethoxy-5-phenylethynyl-phenylsulfanyl)-2-methyl-phenoxy]-acetic    acid;-   {4-[3-(2-Cyclohexyl-ethoxy)-5-phenylethynyl-phenylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   {4-[3-(2-Ethyl-butoxy)-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   {4-[3-Cyclopentyloxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   {4-[3-(2-Cyclohexyl-ethoxy)-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   {4-[3-Cyclopentylmethoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   {4-[3-Cyclopentylmethoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic;-   {4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-benzylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   [4-(3-Isobutoxy-5-phenylethynyl-benzylsulfanyl)-2-methyl-phenoxy]-acetic    acid;-   {4-[3-Isobutoxy-5-(4-methanesulfonyl-phenylethynyl)-benzylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   {4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(5-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   {4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(3-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   {2-Methyl-4-[3-(3-morpholin-4-yl-prop-1-ynyl)-5-(3-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-phenoxy}-acetic    acid;-   {2-Methyl-4-[3-(3-morpholin-4-yl-prop-1-ynyl)-5-(5-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-phenoxy}-acetic    acid;-   {2-Methyl-4-[3-(3-morpholin-4-yl-prop-1-ynyl)-5-(3-trifluoromethyl-phenoxy)-phenylsulfanyl]-phenoxy}-acetic    acid;-   {4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(3-trifluoromethyl-phenoxy)-phenyl-sulfanyl]-2-methyl-phenoxy}-acetic    acid; and-   {2-Methyl-4-[3-phenylethynyl-5-(5-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-phenoxy}-acetic    acid,

or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a novel compoundof formula III:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is C₁₋₄alkyl substituted with 1-2 R^(1a);

R^(1a), at each occurrence, is selected from aryl substituted with 0-2R^(1b), heteroaryl substituted with 0-2 R^(1b), C₃₋₁₀ cycloalkylsubstituted with 0-2 R^(1b), and a heterocycle substituted with 0-2R^(1b)

R^(1b), at each occurrence, is selected from OH substituted with 0-1R^(1c), SH substituted with 0-1 R^(1c), Cl, F, NH₂ substituted with 0-2R^(1c), —CN, NO₂, C₁₋₄alkyl substituted with 0-2 R^(1c), C₂₋₄alkenylsubstituted with 0-2 R^(1c), aryl substituted with 0-2 R^(1c),heteroaryl substituted with 0-2 R^(1c), C₃₋₆cycloalkyl substituted with0-2 R^(1c), and a heterocycle substituted with 0-2 R^(1c);

R^(1c), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, and C₂₋₄alkenyl, aryl substituted with 0-2 R^(1d),heteroaryl substituted with 0-2 R^(1d), C₃₋₆cycloalkyl substituted with0-2 R^(1d), and a heterocycle substituted with 0-2 R^(1d);

R^(1d), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, and C₂₋₄alkenyl;

R^(2a) is selected from aryl substituted with 0-2 R^(2b) and heteroarylsubstituted with 0-2 R^(2b);

R^(2b), at each occurrence, is selected from OH substituted with 0-1R^(2c), SH substituted with 0-1 R^(2c), Cl, F, NH₂ substituted with 0-2R^(2c), —CN, NO₂, C₁₋₄ alkyl substituted with 0-2 R^(2c), C₂₋₄alkenylsubstituted with 0-2 R^(2c), aryl substituted with 0-2 R^(2c),heteroaryl substituted with 0-2 R^(2c), C₃₋₆cycloalkyl substituted with0-2 R^(2c), and a heterocycle substituted with 0-2 R^(2c);

R^(2c), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄alkyl, C₂₋₄ alkenyl, aryl substituted with 0-2 R^(2d), andheteroaryl substituted with 0-2 R^(2d);

R^(2d), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, and C₂₋₄ alkenyl;

R³ is selected from Cl, F, CH₃, and CH₂ CH₃;

alternatively, R³ and R^(5e) combine to form a 5, 6, or 7 membered ringconsisting of carbon atoms and 0-2 heteroatoms selected from O, N, andS(O)₀₋₂ and there are 0-2 ring double bonds in the bridging portionformed by R³ and R^(5e);

R^(4a), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(4b), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(4c), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(5a), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(5b), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(5c), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(5d), at each occurrence, is selected from H, Cl, F, and CH₃; and,

R^(5e), at each occurrence, is selected from H, Cl, F, and CH₃.

In another embodiment, the present invention provides a novel compoundof formula III or a pharmaceutically acceptable salt thereof, wherein:

R¹ is C₁₋₄ alkyl substituted with 1-2 R^(1a);

R^(1a), at each occurrence, is selected from aryl substituted with 0-2R^(1b), 5-10 membered heteroaryl substituted with 0-2 R^(1b) andconsisting of carbon atoms and 1-4 heteroatoms selected from O, N, andS(O)₀₋₂, C₃₋₁₀ cycloalkyl substituted with 0-2 R^(1b), and a 3-8membered heterocycle substituted with 0-2 R^(1b) and consisting ofcarbon atoms and 1-2 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(1b), at each occurrence, is selected from OH substituted with 0-1R^(1c), SH substituted with 0-1 R^(1c), Cl, F, NH₂ substituted with 0-2R^(1c), —CN, NO₂, C₁₋₄ alkyl substituted with 0-2 R^(1c), C₂₋₄alkenylsubstituted with 0-2 R^(1c), aryl substituted with 0-2 R^(1c), 5-10membered heteroaryl substituted with 0-2 R^(1c) and consisting of carbonatoms and 1-4 heteroatoms selected from O, N, and S(O)₀₋₂,C₃₋₆cycloalkyl substituted with 0-2 R^(1c), and a 3-6 memberedheterocycle substituted with 0-2 R^(1c) and consisting of carbon atomsand 1-2 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(1c), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, and C₂₋₄alkenyl, aryl substituted with 0-2 R^(1d), 5-10membered heteroaryl substituted with 0-2 R^(1d) and consisting of carbonatoms and 1-4 heteroatoms selected from O, N, and S(O)₀₋₂, C₃₋₆cycloalkyl substituted with 0-2 R^(1d), and a 3-6 membered heterocyclesubstituted with 0-2 R^(1d) and consisting of carbon atoms and 1-2heteroatoms selected from O, N, and S(O)₀₋₂;

R^(1d), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, and C₂₋₄ alkenyl;

R^(2a) is selected from aryl substituted with 0-2 R^(2b) and 5-10membered heteroaryl substituted with 0-2 R^(2b) and consisting of carbonatoms and 1-4 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(2b), at each occurrence, is selected from OH substituted with 0-1R^(2c), SH substituted with 0-1 R^(2c), Cl, F, NH₂ substituted with 0-2R^(2c), —CN, NO₂, C₁₋₄ alkyl substituted with 0-2 R^(2c), C₂₋₄alkenylsubstituted with 0-2 R^(2c), aryl substituted with 0-2 R^(2c), 5-10membered heteroaryl substituted with 0-2 R^(2c) and consisting of carbonatoms and 1-4 heteroatoms selected from O, N, and S(O)₀₋₂,C₃₋₆cycloalkyl substituted with 0-2 R^(2c), and a 3-6 memberedheterocycle substituted with 0-2 R^(2c) and consisting of carbon atomsand 1-2 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(2c), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, C₂₋₄ alkenyl, aryl substituted with 0-2 R^(2d), and5-10 membered heteroaryl substituted with 0-2 R^(2d) and consisting ofcarbon atoms and 1-4 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(2d), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, and C₂₋₄ alkenyl;

R³ is selected from Cl, F, CH₃, and CH₂ CH₃;

alternatively, R³ and R^(5e) combine to form a 5, 6, or 7 membered ringconsisting of carbon atoms and 0-2 heteroatoms selected from O, N, andS(O)₀₋₂ and there are 0-2 ring double bonds in the bridging portionformed by R³ and R^(5e);

R^(4a), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(4b), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(4c), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(5a), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(5b), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(5c), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(5d), at each occurrence, is selected from H, Cl, F, and CH₃; and,

R^(5e), at each occurrence, is selected from H, Cl, F, and CH₃.

In another embodiment, the present invention provides a novel compoundof formula IIIa

or a pharmaceutically acceptable salt thereof, wherein:

R^(1a), at each occurrence, is selected from aryl substituted with 0-2R^(1b), heteroaryl substituted with 0-2 R^(1b), C₅₋₆cycloalkylsubstituted with 0-2 R^(1b), and a heterocycle substituted with 0-2R^(1b);

R^(1b), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl substituted with 0-2 R^(1c), C₂₋₄ alkenyl substitutedwith 0-2 R^(1c), aryl substituted with 0-2 R^(1c), heteroarylsubstituted with 0-2 R^(1c), C₅₋₆cycloalkyl substituted with 0-2 R^(1c),and a heterocycle substituted with 0-2 R^(1c)

R^(1c), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, and C₂₋₄alkenyl, aryl substituted with 0-2 R^(1d),heteroaryl substituted with 0-2 R^(d), C₃₋₆cycloalkyl substituted with0-2 R^(1d), and a heterocycle substituted with 0-2 R^(d);

R^(2a) is selected from aryl substituted with 0-2 R^(2b) and heteroarylsubstituted with 0-2 R^(2b) and;

R^(2b), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, C₂₋₄ alkenyl, aryl, heteroaryl, C₅₋₆cycloalkyl, and aheterocycle.

In another embodiment, the present invention provides a novel compoundof formula IIIa or a pharmaceutically acceptable salt thereof, wherein:

R^(1a), at each occurrence, is selected from aryl substituted with 0-2R^(1b), 5-6 membered heteroaryl substituted with 0-2 R^(1b) andconsisting of carbon atoms and 1-2 heteroatoms selected from O, N, andS(O)₀₋₂, C₅₋₆cycloalkyl substituted with 0-2 R^(1b), and a 5-6 memberedheterocycle substituted with 0-2 R^(1b) and consisting of carbon atomsand 1-2 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(1b), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl substituted with 0-2 R^(1c), C₂₋₄ alkenyl substitutedwith 0-2 R^(1c), aryl substituted with 0-2 R^(1c), 5-6 memberedheteroaryl substituted with 0-2 R^(1c) and consisting of carbon atomsand 1-2 heteroatoms selected from O, N, and S(O)₀₋₂, C₅₋₆cycloalkylsubstituted with 0-2 R^(1c), and a 5-6 membered heterocycle substitutedwith 0-2 R^(1c) and consisting of carbon atoms and 1-2 heteroatomsselected from O, N, and S(O)₀₋₂;

R^(1c), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, and C₂₋₄alkenyl, aryl substituted with 0-2 R^(1d), 5-6membered heteroaryl substituted with 0-2 R^(1d) and consisting of carbonatoms and 1-2 heteroatoms selected from O, N, and S(O)₀₋₂,C₃₋₆cycloalkyl substituted with 0-2 R^(1d), and a 3-6 memberedheterocycle substituted with 0-2 R^(1d) and consisting of carbon atomsand 1-2 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(2a) is selected from aryl substituted with 0-2 R^(2b) and 5-6membered heteroaryl substituted with 0-2 R^(2b) and consisting of carbonatoms and 1-2 heteroatoms selected from O, N, and S(O)₀₋₂; and,

R^(2b), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, C₂₋₄ alkenyl, aryl, 5-6 membered heteroaryl consistingof carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)₀₋₂,C₅₋₆cycloalkyl, and a 5-6 membered heterocycle and consisting of carbonatoms and 1-2 heteroatoms selected from O, N, and S(O)₀₋₂.

In another embodiment, the present invention provides a novel compoundof formula Ia, wherein:

R¹ is C₁₋₄ alkyl substituted with 1-2 R^(1a);

R^(1a), at each occurrence, is selected from aryl substituted with 0-2R^(1b), heteroaryl substituted with 0-2 R^(1b), C₃₋₁₀ cycloalkylsubstituted with 0-2 R^(1b), and a heterocycle substituted with 0-2R^(1b);

R^(1b), at each occurrence, is selected from OH substituted with 0-1R^(1c), SH substituted with 0-1 R^(1c), Cl, F, NH₂ substituted with 0-2R^(1c), —CN, NO₂, C₁₋₄ alkyl substituted with 0-2 R^(1c), C₂₋₄alkenylsubstituted with 0-2 R^(1c), aryl substituted with 0-2 R^(1c),heteroaryl substituted with 0-2 R^(1c), C₃₋₆cycloalkyl substituted with0-2 R^(1c), and a heterocycle substituted with 0-2 R^(1c);

R^(1c), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, and C₂₋₄alkenyl, aryl substituted with 0-2 R^(1d),heteroaryl substituted with 0-2 R^(1d), C₃₋₆cycloalkyl substituted with0-2 R^(1d), and a heterocycle substituted with 0-2 R^(1d);

R^(1d), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, and C₂₋₄ alkenyl;

R² is aryl substituted with 0-3 R^(2a) or heteroaryl substituted with0-2 R^(2a)

R^(2a), at each occurrence, is selected from OH substituted with 0-1R^(2b), SH substituted with 0-1 R^(2b), Cl, F, NH₂ substituted with 0-2R^(2b), —CN, NO₂, C₁₋₄ alkyl substituted with 0-2 R^(2b), C₂₋₆alkenylsubstituted with 0-2 R^(2b), aryl substituted with 0-2 R^(2b),heteroaryl substituted with 0-2 R^(2b), C₃₋₆cycloalkyl substituted with0-2 R^(2b), and a heterocycle substituted with 0-2 R^(2b);

R^(2b), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, and, C₂₋₄ alkenyl;

R³ is selected from Cl, F, CH₃, and CH₂ CH₃;

alternatively, R³ and R^(5e) combine to form a 5, 6, or 7 membered ringconsisting of carbon atoms and 0-2 heteroatoms selected from O, N, andS(O)₀₋₂ and there are 0-2 ring double bonds in the bridging portionformed by R³ and R^(5e);

R^(4a), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(4b), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(4c), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(5a), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(5b), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(5c), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(5d), at each occurrence, is selected from H, Cl, F, and CH₃; and,

R^(5e), at each occurrence, is selected from H, Cl, F, and CH₃.

In another embodiment, the present invention provides a novel compoundof formula Ia, wherein:

R¹ is C₁₋₄ alkyl substituted with 1-2 R^(1a);

R^(1a), at each occurrence, is selected from aryl substituted with 0-2R^(1b), 5-10 membered heteroaryl substituted with 0-2 R^(1b) andconsisting of carbon atoms and 1-4 heteroatoms selected from O, N, andS(O)₀₋₂, C₃₋₁₀ cycloalkyl substituted with 0-2 R^(1b), and a 3-8membered heterocycle substituted with 0-2 R^(1b) and consisting ofcarbon atoms and 1-2 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(1b), at each occurrence, is selected from OH substituted with 0-1R^(1c), SH substituted with 0-1 R^(1c), Cl, F, NH₂ substituted with 0-2R^(1c), —CN, NO₂, C₁₋₄ alkyl substituted with 0-2 R^(1c), C₂₋₄alkenylsubstituted with 0-2 R^(1c), aryl substituted with 0-2 R^(1c), 5-10membered heteroaryl substituted with 0-2 R^(1c) and consisting of carbonatoms and 1-4 heteroatoms selected from O, N, and S(O)₀₋₂,C₃₋₆cycloalkyl substituted with 0-2 R^(1c), and a 3-6 memberedheterocycle substituted with 0-2 R^(1c) and consisting of carbon atomsand 1-2 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(1c), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, and C₂₋₄alkenyl, aryl substituted with 0-2 R^(1d), 5-10membered heteroaryl substituted with 0-2 R^(1d) and consisting of carbonatoms and 1-4 heteroatoms selected from O, N, and S(O)₀₋₂, C₃₋₆cycloalkyl substituted with 0-2 R^(1d), and a 3-6 membered heterocyclesubstituted with 0-2 R^(1d) and consisting of carbon atoms and 1-2heteroatoms selected from O, N, and S(O)₀₋₂;

R^(1d), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, and C₂₋₄ alkenyl;

R² is aryl substituted with 0-3 R^(2a) or 5-10 membered heteroarylsubstituted with 0-2 R^(2a) and consisting of carbon atoms and 1-4heteroatoms selected from O, N, and S(O)₀₋₂;

R^(2a), at each occurrence, is selected from OH substituted with 0-1R^(2b), SH substituted with 0-1 R^(2b), Cl, F, NH₂ substituted with 0-2R^(2b), —CN, NO₂, C₁₋₄ alkyl substituted with 0-2 R^(2b), C₂₋₆alkenylsubstituted with 0-2 R^(2b), aryl substituted with 0-2 R^(2b), 5-10membered heteroaryl substituted with 0-2 R^(2b) and consisting of carbonatoms and 1-4 heteroatoms selected from O, N, and S(O)₀₋₂,C₃₋₆cycloalkyl substituted with 0-2 R^(2b), and a 3-6 memberedheterocycle substituted with 0-2 R^(2b) and consisting of carbon atomsand 1-2 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(2b), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, and, C₂₋₄alkenyl;

R³ is selected from Cl, F, CH₃, and CH₂ CH₃;

alternatively, R³ and R^(5e) combine to form a 5, 6, or 7 membered ringconsisting of carbon atoms and 0-2 heteroatoms selected from O, N, andS(O)₀₋₂ and there are 0-2 ring double bonds in the bridging portionformed by R³ and R^(5e);

R^(4a), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(4b), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(4c), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(5a), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(5b), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(5c), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(5d), at each occurrence, is selected from H, Cl, F, and CH₃; and,

R^(5e), at each occurrence, is selected from H, Cl, F, and CH₃.

In another embodiment, the present invention provides a novel compoundof formula Ib:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is C₁₋₄ alkyl substituted with 1 R^(1a);

R^(1a), at each occurrence, is selected from aryl substituted with 0-2R^(1b), 5-6 membered heteroaryl substituted with 0-2 R^(1b) andconsisting of carbon atoms and 1-2 heteroatoms selected from O, N, andS(O)₀₋₂, C₅₋₆cycloalkyl substituted with 0-2 R^(1b), and a 5-6 memberedheterocycle substituted with 0-2 R^(1b) and consisting of carbon atomsand 1-2 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(1b), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl substituted with 0-2 R^(1c), C₂₋₄ alkenyl substitutedwith 0-2 R^(1c), aryl substituted with 0-2 R^(1c), 5-6 memberedheteroaryl substituted with 0-2 R^(1c) and consisting of carbon atomsand 1-2 heteroatoms selected from O, N, and S(O)₀₋₂, C₅₋₆cycloalkylsubstituted with 0-2 R^(1c), and a 5-6 membered heterocycle substitutedwith 0-2 R^(1c) and consisting of carbon atoms and 1-2 heteroatomsselected from O, N, and S(O)₀₋₂;

R^(1c), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, and C₂₋₄alkenyl, aryl substituted with 0-2 R^(1d), 5-6membered heteroaryl substituted with 0-2 R^(1d) and consisting of carbonatoms and 1-2 heteroatoms selected from O, N, and S(O)₀₋₂,C₃₋₆cycloalkyl substituted with 0-2 R^(1d), and a 3-6 memberedheterocycle substituted with 0-2 R^(1d) and consisting of carbon atomsand 1-2 heteroatoms selected from O, N, and S(O)₀₋₂;

R² is aryl substituted with 0-2 R^(2a) or 5-6 membered heteroarylsubstituted with 0-2 R^(2a) and consisting of carbon atoms and 1-2heteroatoms selected from O, N, and S(O)₀₋₂; and,

R^(2a), at each occurrence, is selected from OH substituted with 0-1R^(2b), SH substituted with 0-1 R^(2b), Cl, F, NH₂ substituted with 0-2R^(2b), —CN, NO₂, C₁₋₄ alkyl substituted with 0-2 R^(2b), C₂₋₆alkenylsubstituted with 0-2 R^(2b), aryl substituted with 0-2 R^(2b), 5-6membered heteroaryl substituted with 0-2 R^(2b) and consisting of carbonatoms and 1-2 heteroatoms selected from O, N, and S(O)₀₋₂,C₅₋₆cycloalkyl substituted with 0-2 R^(2b), and a 5-6 memberedheterocycle substituted with 0-2 R^(2b) and consisting of carbon atomsand 1-2 heteroatoms selected from O, N, and S(O)₀₋₂.

In another embodiment, the present invention provides a novel compoundpharmaceutical composition, comprising: a pharmaceutically acceptablecarrier and a compound of the present invention or a pharmaceuticallyacceptable salt thereof.

In another embodiment, the present invention provides a novel method oftreating type 2 diabetes, comprising: administering a therapeuticallyeffective amount of a compound of the present invention or apharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method oftreating a disease comprising administering to a patient in need thereofa therapeutically effective amount of a compound of the presentinvention or a pharmaceutically acceptable salt thereof, wherein thedisease is selected from dyslipidemia, syndrome X (including themetabolic syndrome, e.g., hypertension, impaired glucose tolerance(IGT), insulin resistance, hypertrigyceridaemia, and obesity),cardiovascular diseases (e.g., atherosclerosis and related diseases,including mortality reduction, coronary artery diseases, coronary heartdiseases, heart attack, myocardial ischemia, myocardial infarct,coronary infarct, transient ischemic attack (TIA), and stroke),hyperglycemia, hyperlipidemia, hypercholesterolemia, andhyperinsulinemia.

In another embodiment, the present invention provides a method oftreating a disease comprising administering to a patient in need thereofa therapeutically effective amount of at least one compound of thepresent invention or a pharmaceutically acceptable salt thereof, whereinthe disease is selected from non-insulin requiring Type 2 diabetes toinsulin requiring Type 2 diabetes, decreasing apoptosis in mammaliancells (e.g., beta cells of Islets of Langerhans), renal diseases (e.g.,glomerulonephritis, glomerulosclerosis, nephrotic syndrome, andhypertensive nephrosclerosis), improving cognitive functions indementia, treating diabetic complications, psoriasis, polycystic ovariansyndrome (PCOS), prevention and treatment of bone loss (e.g.osteoporosis), and lowering the bio-markers of atherosclerosis (e.g.,c-reactive protein (CRP), TNF-α, and IL-6).

In another embodiment, the present invention provides a novel processfor the preparation of the compounds of the present invention orstereoisomers or pharmaceutically acceptable salts thereof.

In another embodiment, the present compounds are administered incombination with one or more further pharmacologically active substancesselected from antiobesity agents, appetite regulating agents,antidiabetics, antihypertensive agents, agents for the treatment ofcomplications resulting from or associated with diabetes, and agents forthe treatment of complications and disorders resulting from orassociated with obesity.

Suitable additional substances may be selected from CART (cocaineamphetamine regulated transcript) agonists, NPY (neuropeptide Y)antagonists, MC4 (melanocortin 4) agonists, orexin antagonists, TNF(tumor necrosis factor) agonists, CRF (corticotropin releasing factor)agonists, CRF BP (corticotropin releasing factor binding protein)antagonists, urocortin agonists, β3 agonists, MSH(melanocyte-stimulating hormone) agonists, MCH (melanocyte-concentratinghormone) antagonists, CCK (cholecystokinin) agonists, serotoninre-uptake inhibitors, serotonin and noradrenaline re-uptake inhibitors,mixed serotonin and noradrenergic compounds, 5HT (serotonin) agonists,bombesin agonists, galanin antagonists, growth hormone, growth hormonereleasing compounds, TRH (thyreotropin releasing hormone) agonists, UCP2 or 3 (uncoupling protein 2 or 3) modulators, leptin agonists, DAagonists (bromocriptin, doprexin), lipase/amylase inhibitors, RXR(retinoid X receptor) modulators or TR β agonists.

Suitable antiobesity agents include leptin, dexamphetamine, amphetamine,fenfluramine, dexfenfluramine, sibutramine, orlistat, mazindol, andphentermine.

Suitable antidiabetics include insulin, orally active hypoglycaemicagents, and GLP-1 (glucagon like peptide-1) derivatives (see WO98/08871).

Orally active hypoglycaemic agents preferably include sulphonylureas,biguanides, meglitinides, glucosidase inhibitors, glucagon antagonists(see WO99/01423), GLP-1 agonists, potassium channel openers (see WO97/26265 and WO 99/03861), DPP-IV (dipeptidyl peptidase-IV) inhibitors,inhibitors of hepatic enzymes involved in stimulation of gluconeogenesisand/or glycogenolysis, glucose uptake modulators, compounds modifyingthe lipid metabolism (e.g., antihyperlipidemic agents and antilipidemicagents), compounds lowering food intake, RXR agonists, agents acting onthe ATP-dependent potassium channel of the β-cells, andthiazolidinediones (e.g., troglitazone, ciglitazone, pioglitazone androsiglitazone).

Agents to be administered in combination with compounds of the presentinvention also include sulphonylureas (e.g., tolbutamide, glibenclamide,glipizide, and glicazide), biguanides (e.g., metformin), meglitinides(e.g., repaglinide and senaglinide), α-glucosidase inhibitors (e.g.,miglitol and acarbose), an agent acting on the ATP-dependent potassiumchannel of the β-cells (e.g., the above sulphonylureas and repaglinide),and nateglinide.

Antihyperlipidemic or antilipidemic agents include apolipoprotein A-IMilano, cholestyramine, colestipol, clofibrate, gemfibrozil,fenofibrate, bezafibrate, tesaglitazar, muraglitazar, EML-4156,LY-518674, LY-519818, MK-767, torcetrapib, atorvastatin, fluvastatin,lovastatin, pravastatin, simvastatin, cerivastin, rosuvastatin,pitavastatin, acipimox, ezetimibe, probucol, dextrothyroxine andnicotinic acid.

In another embodiment the present compounds are administered incombination with more than one of the above-mentioned compounds (e.g, incombination with a sulphonylurea and metformin, a sulphonylurea andacarbose, repaglinide and metformin, insulin and a sulphonylurea,insulin and metformin, or insulin and lovastatin).

Examples of antihypertensive agents include β-blockers (e.g, alprenolol,atenolol, timolol, pindolol, propranolol, and metoprolol), ACE(angiotensin converting enzyme) inhibitors (e.g., benazepril, captopril,enalapril, fosinopril, lisinopril, quinapril and ramipril), calciumchannel blockers (e.g., nifedipine, felodipine, nicardipine, isradipine,nimodipine, diltiazem and verapamil), and α-blockers (e.g., doxazosin,urapidil, prazosin and terazosin).

It should be understood that any suitable combination of the compoundsaccording to the invention with one or more of the above-mentionedcompounds and optionally one or more further pharmacologically activesubstances are considered to be within the scope of the presentinvention.

It is preferred that the compounds of the present invention have asolubility in water of at least 0.1 mg/L as determined at 25° C. and pH7.0. More preferably the solubility is at least 0.5 mg/L. Even morepreferably the solubility is at least 1 mg/L. Still more preferably, thesolubility is at least 2 mg/L. Further preferably the solubility is atleast 10 mg/L. Even further preferably the solubility is at least 50mg/L. Still further preferably the solubility is at least 200 mg/L.

It is preferred that compounds of the present invention have an IC₅₀value of less than 5 μm as determined by the PPAR transienttransactivation assay. More preferably the IC₅₀ value is less than 1 μm.Even more preferably the IC₅₀ value is less than 500 nM. Still morepreferably the IC₅₀ value is less than 100 nM. Further preferably theIC₅₀ value is less than 50 nM. Even further preferably the IC₅₀ value isless than 25 nM. Still further preferably the IC₅₀ value is less than 10nM. Even still further preferably the IC₅₀ value is less than 5 nM.

It is preferred that the compounds of the present invention have amolecular weight of less than 1000 g/mol. More preferably the molecularweight is less than 750 g/mol. Even more preferably the molecular weightis less than 600 g/mol. Still more preferably, the molecular weight isless than 550 g/mol. Further preferably the molecular weight is lessthan 500 g/mol. Even further preferably the molecular weight is lessthan 400 g/mol.

It is preferred that compounds of the present invention are ionized atpH 7.4.

It is preferred that the compounds of the present invention have onlyone ionized carboxylic acid group at a pH of from 5.5-9. More preferablythe compounds have only one ionized carboxylic acid group at a pH offrom 6-8. Even more preferably the compounds have only one ionizedcarboxylic acid group at a pH of from 6.5-7.5. Still more preferably,the compounds have only one ionized carboxylic acid group at pH 7.4.

It is preferred that the compounds of the present invention arezwitter-ionic with one ionized amine group and one ionized carboxylicacid group at a pH of from 5.5-9. More preferably the compounds arezwitter-ionic with one ionized amine group and one ionized carboxylicacid group at a pH of from 6-8. Even more preferably the compounds arezwitter-ionic with one ionized amine group and one ionized carboxylicacid group at a pH of from 6.5-7.5. Still more preferably, the compoundsare zwitter-ionic with one ionized amine group and one ionizedcarboxylic acid group at pH 7.4.

Pharmaceutical Compositions

The compounds of the invention may be administered alone or incombination with pharmaceutically acceptable carriers or excipients, ineither single or multiple doses. The pharmaceutical compositions of thepresent invention may be formulated with pharmaceutically acceptablecarriers or diluents as well as any other known adjuvants and excipientsin accordance with conventional techniques such as those disclosed inRemington: The Science and Practice of Pharmacy, 19^(th) Edition,Gennaro, Ed., Mack Publishing Co., Easton, Pa., 1995. The compositionsmay appear in conventional forms, which include capsules, tablets,aerosols, solutions, suspensions, and topical applications.

Typical compositions include a compound of the present invention apharmaceutically acceptable acid addition salt thereof, associated witha pharmaceutically acceptable excipient, which may be a carrier or adiluent or be diluted by a carrier, or enclosed within a carrier, whichcan be in the form of a capsule, sachet, paper, or other container. Inmaking the compositions, conventional techniques for the preparation ofpharmaceutical compositions may be used. For example, the activecompound will usually be mixed with a carrier, or diluted by a carrier,or enclosed within a carrier which may be in the form of a ampoule,capsule, sachet, paper, or other container. When the carrier serves as adiluent, it may be solid, semi-solid, or liquid material which acts as avehicle, excipient, or medium for the active compound. The activecompound can be adsorbed on a granular solid container for example in asachet. Some examples of suitable carriers are water, salt solutions,alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil,peanut oil, olive oil, gelatine, lactose, terra alba, sucrose,cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin,acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid,fatty acids, fatty acid amines, fatty acid monoglycerides anddiglycerides, pentaerythritol fatty acid esters, polyoxyethylene,hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, the carrieror diluent may include any sustained release material known in the art,such as glyceryl monostearate or glyceryl distearate, alone or mixedwith a wax. The formulations may also include wetting agents,emulsifying and suspending agents, preserving agents, sweetening agentsor flavouring agents. The formulations of the invention may beformulated so as to provide quick, sustained, or delayed release of theactive ingredient after administration to the patient by employingprocedures well known in the art.

The pharmaceutical compositions can be sterilized and mixed, if desired,with auxiliary agents, emulsifiers, salt for influencing osmoticpressure, buffers and/or colouring substances and the like, which do notdeleteriously react with the active compounds.

The route of administration may be any route, which effectivelytransports the active compound to the appropriate or desired site ofaction, such as oral, nasal, pulmonary, transdermal or parenteral e.g.rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular,intranasal, ophthalmic solution or an ointment, the oral route beingpreferred.

If a solid carrier is used for oral administration, the preparation maybe tabletted, placed in a hard gelatin capsule in powder or pellet formor it can be in the form of a troche or lozenge. If a liquid carrier isused, the preparation may be in the form of a syrup, emulsion, softgelatin capsule or sterile injectable liquid such as an aqueous ornon-aqueous liquid suspension or solution.

For nasal administration, the preparation may contain a compound offormula I dissolved or suspended in a liquid carrier, in particular anaqueous carrier, for aerosol application. The carrier may containadditives such as solubilizing agents, e.g. propylene glycol,surfactants, absorption enhancers such as lecithin (phosphatidylcholine)or cyclodextrin, or preservatives such as parabenes.

For parenteral application, particularly suitable are injectablesolutions or suspensions, preferably aqueous solutions with the activecompound dissolved in polyhydroxylated castor oil.

Tablets, dragees, or capsules having talc and/or a carbohydrate carrieror binder or the like are particularly suitable for oral application.Preferable carriers for tablets, dragees, or capsules include lactose,corn starch, and/or potato starch. A syrup or elixir can be used incases where a sweetened vehicle can be employed.

If desired, the pharmaceutical composition of the invention may comprisea compound of the present invention in combination with furtherpharmacologically active substances such as those described in theforegoing.

The compounds of the invention may be administered to a mammal,especially a human in need of such treatment, prevention, elimination,alleviation or amelioration of diseases related to the regulation ofblood sugar. Mammals also include animals, both domestic animals, e.g.household pets, and non-domestic animals such as wildlife.

The compounds of the present invention are expected to be effective overa wide dosage range. A typical oral dosage is in the range of from about0.001 to about 100 mg/kg body weight per day, preferably from about 0.01to about 50 mg/kg body weight per day, and more preferred from about0.05 to about 10 mg/kg body weight per day administered in one or moredosages such as 1 to 3 dosages. The exact dosage will depend upon thefrequency and mode of administration, the sex, age, weight and generalcondition of the subject treated, the nature and severity of thecondition treated and any concomitant diseases to be treated and otherfactors evident to those skilled in the art.

The formulations may conveniently be presented in unit dosage form bymethods known to those skilled in the art. A typical unit dosage formfor oral administration one or more times per day such as 1 to 3 timesper day may contain of from 0.05 to about 1000 mg, preferably from about0.1 to about 500 mg, and more preferred from about 0.5 mg to about 200mg.

DEFINITIONS

All references described herein are incorporated in there entirety byreference.

“Substituted” signifies that one or more hydrogen atoms are replaced bythe designated substituent. Only pharmaceutically stable compounds areintended to be covered.

When examples of definitions are provided, the definition is not meantto be limited to the specific examples.

The present invention includes all isotopes of atoms occurring in thepresent compounds. Isotopes include those atoms having the same atomicnumber but different mass numbers. By way of general example and withoutlimitation, isotopes of hydrogen include tritium and deuterium. Isotopesof carbon include C-13 and C-14.

When O or S is listed as a substituent, oxo and sulfo, respectively, itis intended that a carbon atom be replaced by either the O or S. Forexample if alkyl were substituted by O, then an ether would be formed.Preferably heteroatom-heteroatom bonds such as O—O, O—S, O—N, S—S, andS—N are not formed.

“Alkyl” includes both straight chain and branched alkyl groups havingthe designated number of carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, or 8).Examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, s-butyl, t-butyl, 2-methyl-butyl, and 2-ethyl-butyl.

“Alkenyl” includes both straight chain and branched alkenyll groupshaving the designated number of carbon atoms (e.g., 2, 3, 4, 5, 6, 7, or8). Examples of alkenyl groups include ethenyl, 1-propenyl, 2-propenyl,1-butenyl, 2-butenyl, and 2-methyl-butenyl.

“Alkynyl” includes both straight chain and branched alkynyl groupshaving the designated number of carbon atoms (e.g., 2, 3, 4, 5, 6, 7, or8). Examples of alkynyl groups include ethynyl, 1-propynyl, 2-propynyl,1-butynyl, 2-butynyl, and 2-methyl-butynyl.

“Aryl” includes phenyl, naphthyl, fluorene, anthracene, phenanthrenyl,azulenyl, and a partially saturated bicyclic carbocyclic ring. Thepartially saturated bicyclic carbocyclic ring consists of 8, 9, 10, 11,or 12 carbon atoms, preferably 8, 9, or 10 carbon atoms. Examples ofpartially saturated bicyclic carbocyclic rings include1,2,3,4-tetrahydronaphthyl, indanyl, indenyl,1,2,4α,5,8,8α-hexahydronaphtyl, and 1,3α-dihydropentalene. A preferredaryl group is phenyl.

“Cycloalkyl” means a ring having the number of designated carbon atomsand having only single bonds between the carbon atoms. Examples ofcycloalkyl include, but are not limited to cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and cycloheptyl. Preferred cycloalkyl groupsare cyclopentyl and cyclohexyl.

“Heteroaryl” signifies a mono-, bi-, or tricyclic ring consisting ofcarbon atoms and from one heteroatom to 5, wherein the heteroatom isselected from oxygen, nitrogen, and sulphur. If sulphur is present, thenit can be mono- or di-oxidized. If a nitrogen is present, then it can beN, NH, or substituted N. The heterocycle can be attached via a carbon ornitrogen atom, unless linking the nitrogen atom would lead to aquaternary nitrogen. If the heteroaryl is bicyclic, then one or both ofthe rings may have a heteroatom(s) present. If the heteroaryl istricyclic, then one, two, or all three of the rings may have aheteroatom(s) present. If the heterocycle is monocyclic, then this ringis aromatic (e.g., fully unsaturated). If the heteroaryl is bicyclic ortricyclic, then at least one ring is aromatic.

Examples of “heteroaryl” are pyrrolyl (e.g. pyrrol-1-yl, pyrrol-2-yl,pyrrol-3-yl), furanyl (e.g. furan-2-yl, furan-3-yl), thienyl (e.g.thien-2-yl, thien-3-yl), oxazolyl (e.g. oxazol-2-yl, oxazol-4-yl,oxazol-5-yl), thiazolyl (e.g. thiazol-2-yl, thiazol-4-yl, thiazol-5-yl),imidazolyl (e.g. imidazol-2-yl, imidazol-4-yl, imidazol-5-yl), pyrazolyl(e.g. pyrazol-1-yl, pyrazol-3-yl, pyrazol-5-yl), isoxazolyl (e.g.isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl), isothiazolyl (e.g.isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl), 1,2,3-triazolyl(e.g. 1,2,3-triazol-1-yl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl),1,2,4-triazolyl (e.g. 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl,1,2,4-triazol-5-yl), 1,2,3-oxadiazolyl (e.g. 1,2,3-oxadiazol-4-yl,1,2,3-oxadiazol-5-yl), 1,2,4-oxadiazolyl (e.g. 1,2,4-oxadiazol-3-yl,1,2,4-oxadiazol-5-yl), 1,2,5-oxadiazolyl (e.g. 1,2,5-oxadiazol-3-yl,1,2,5-oxadiazol-4-yl), 1,3,4-oxadiazolyl (e.g. 1,3,4-oxadiazol-2-yl,1,3,4-oxadiazol-5-yl), 1,2,3-thiadiazolyl (e.g. 1,2,3-thiadiazol-4-yl,1,2,3-thiadiazol-5-yl), 1,2,4-thiadiazolyl (e.g. 1,2,4-thiadiazol-3-yl,1,2,4-thiadiazol-5-yl), 1,2,5-thiadiazolyl (e.g. 1,2,5-thiadiazol-3-yl,1,2,5-thiadiazol-4-yl), 1,3,4-thiadiazolyl (e.g. 1,3,4-thiadiazol-2-yl,1,3,4-thiadiazol-5-yl), tetrazolyl (e.g. tetrazol-1-yl, tetrazol-5-yl),pyranyl (e.g. pyran-2-yl), pyridinyl (e.g. pyridine-2-yl, pyridine-3-yl,pyridine-4-yl), pyridazinyl (e.g. pyridazin-2-yl, pyridazin-3-yl),pyrimidinyl (e.g. pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl),pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl,thiadiazinyl, azepinyl, azecinyl, indolyl (e.g. indol-1-yl, indol-2-yl,indol-3-yl, indol-5-yl), isoindolyl, benzofuranyl (e.g.benzo[b]furan-2-yl, benzo[b]furan-3-yl, benzo[b]furan-5-yl,benzo[c]furan-2-yl, benzo[c]furan-3-yl, benzo[c]furan-5-yl),benzothienyl (e.g. benzo[b]thien-2-yl, benzo[b]thien-3-yl,benzo[b]thien-5-yl, benzo[c]thien-2-yl, benzo[c]thien-3-yl,benzo[c]thien-5-yl), indazolyl (e.g. indazol-1-yl, indazol-3-yl,indazol-5-yl), indolizinyl (e.g. indolizin-1-yl, indolizin-3-yl),benzopyranyl (e.g. benzo[b]pyran-3-yl, benzo[b]pyran-6-yl,benzo[c]pyran-1-yl, benzo[c]pyran-7-yl), benzimidazolyl (e.g.benzimidazol-1-yl, benzimidazol-2-yl, benzimidazol-5-yl), benzothiazolyl(e.g. benzothiazol-2-yl, benzothiazol-5-yl), benzisothiazolyl,benzoxazolyl, benzisoxazolyl, benzoxazinyl, benzotriazolyl,naphthyridinyl (e.g. 1,8-naphthyridin-2-yl, 1,7-naphthyridin-2-yl,1,6-naphthyridin-2-yl), phthalazinyl (e.g. phthalazin-1-yl,phthalazin-5-yl), pteridinyl, purinyl (e.g. purin-2-yl, purin-6-yl,purin-7-yl, purin-8-yl, purin-9-yl), quinazolinyl (e.g. quinazolin-2-yl,quinazolin-4-yl, quinazolin-6-yl), cinnolinyl, quinoliny (e.g.quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-6-yl),isoquinolinyl (e.g. isoquinolin-1-yl, isoquinolin-3-yl,isoquinolin-4-yl), quinoxalinyl (e.g. quinoxalin-2-yl, quinoxalin-5-yl),pyrrolopyridinyl (e.g. pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-c]pyridinyl,pyrrolo[3,2-c]pyridinyl), furopyridinyl (e.g. furo[2,3-b]pyridinyl,furo[2,3-c]pyridinyl, furo[3,2-c]pyridinyl), thienopyridinyl (e.g.thieno[2,3-b]pyridinyl, thieno[2,3-c]pyridinyl, thieno[3,2-c]pyridinyl),imidazopyridinyl (e.g. imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl,imidazo[1,5-a]pyridinyl, imidazo[1,2-a]pyridinyl), imidazopyrimidinyl(e.g. imidazo[1,2-a]pyrimidinyl, imidazo[3,4-a]pyrimidinyl),pyrazolopyridinyl (e.g. pyrazolo[3,4-b]pyridinyl,pyrazolo[3,4-c]pyridinyl, pyrazolo[1,5-a]pyridinyl), pyrazolopyrimidinyl(e.g. pyrazolo[1,5-a]pyrimidinyl, pyrazolo[3,4-d]pyrimidinyl),thiazolopyridinyl (e.g. thiazolo[3,2-d]pyridinyl), thiazolopyrimidinyl(e.g. thiazolo[5,4-d]pyrimidinyl), imdazothiazolyl (e.g.imidazo[2,1-b]thiazolyl), triazolopyridinyl (e.g.triazolo[4,5-b]pyridinyl), triazolopyrimidinyl (e.g. 8-azapurinyl),carbazolyl (e.g. carbazol-2-yl, carbazol-3-yl, carbazol-9-yl),phenoxazinyl (e.g. phenoxazin-10-yl), phenazinyl (e.g. phenazin-5-yl),acridinyl (e.g. acridin-9-yl, acridin-10-yl), phenothiazinyl (e.g.phenothiazin-10-yl), carbolinyl (e.g. pyrido[3,4-b]indol-1-yl,pyrido[3,4-b]indol-3-yl), phenanthrolinyl (e.g. phenanthrolin-5-yl),pyrrolinyl, pyrazolinyl, imidazolinyl (e.g. 4,5-dihydroimidazol-2-yl,4,5-dihydroimidazol-1-yl), indolinyl (e.g. 2,3-dihydroindol-1-yl,2,3-dihydroindol-5-yl), dihydrobenzofuranyl (e.g.2,3-dihydrobenzo[b]furan-2-yl, 2,3-dihydrobenzo[b]furan-4-yl),dihydrobenzothienyl (e.g. 2,3-dihydrobenzo[b]thien-2-yl,2,3-dihydrobenzo[b]thien-5-yl), 4,5,6,7-tetrahydrobenzo[b]furan-5-yl),dihydrobenzopyranyl (e.g. 3,4-dihydrobenzo[b]pyran-3-yl,3,4-dihydrobenzo[b]pyran-6-yl, 3,4-dihydrobenzo[c]pyran-1-yl,dihydrobenzo[c]pyran-7-yl), oxazolinyl (e.g. 4,5-dihydrooxazol-2-yl,4,5-dihydrooxazol-4-yl, 4,5-dihydrooxazol-5-yl), isoxazolinyl,oxazepinyl, tetrahydroindazolyl (e.g. 4,5,6,7-tetrahydroindazol-1-yl,4,5,6,7-tetrahydroindazol-3-yl, 4,5,6,7-tetrahydroindazol-4-yl,4,5,6,7-tetrahydroindazol-6-yl), tetrahydrobenzimidazolyl (e.g.4,5,6,7-tetrahydrobenzimidazol-1-yl,4,5,6,7-tetrahydrobenzimidazol-5-yl), tetrahydroimidazo[4,5-c]pyridyl(e.g. 4,5,6,7-tetrahydroimidazo[4,5-c]pyrid-1-yl,4,5,6,7-tetrahydroimidazo[4,5-c]pyrid-5-yl,4,5,6,7-tetrahydroimidazo[4,5-c]pyrid-6-yl), tetrahydroquinolinyl (e.g.1,2,3,4-tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinolinyl),tetrahydroisoquinolinyl (e.g. 1,2,3,4-tetrahydroisoquinolinyl,5,6,7,8-tetrahydroisoquinolinyl), tetrahydroquinoxalinyl (e.g.1,2,3,4-tetrahydroquinoxalinyl, 5,6,7,8-tetrahydroquinoxalinyl),spiro[isoquinoline-3,1′-cyclohexan]-1-yl,spiro[piperidine-4,1′-benzo[c]thiophen]-1-yl,spiro[piperidine-4,1′-benzo[c]furan]-1-yl,spiro[piperidine-4,3′-benzo[b]furan]-1-yl,spiro[piperidine-4,3′-coumarin]-1-yl. A preferred heteroaryl ispyridinyl.

Other examples of “heteroaryl” are furyl, thienyl, pyrrolyl, imidazolyl,pyrazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, quinolyl,isoquinolyl, quinazolinyl, quinoxalinnyl, indolyl, benzimidazolyl,benzofuranyl, benzothienyl, pteridinyl and purinyl.

“Heterocyclyl” or “heterocycle” (heterocycle) signifies a mono-, bi-, ortricyclic ring consisting of carbon atoms and from one heteroatom to 4,wherein the heteroatom is selected from oxygen, nitrogen, and sulphur.If sulphur is present, then it can be S, S(O), or S(O)₂. If nitrogen ispresent, then it can be N, NH, substituted N, or N-oxide. Theheterocycle is a saturated or partially saturated ring. From 0-2 CH₂groups of the heterocycle can be replaced by C(O). The heterocycle canbe attached via a carbon or nitrogen atom, unless linking the nitrogenatom would lead to a quaternary nitrogen. If the heterocycle isbicyclic, then one or both of the rings may have a heteroatom(s)present. If the heterocycle is tricyclic, then one, two, or all three ofthe rings may have a heteroatom(s) present.

Examples of “heterocycle” are aziridinyl (e.g. aziridin-1-yl),azetidinyl (e.g. azetidin-1-yl, azetidin-3-yl), oxetanyl, pyrrolidinyl(e.g. pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl), imidazolidinyl(e.g. imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-4-yl),oxazolidinyl (e.g. oxazolidin-2-yl, oxazolidin-3-yl, oxazolidin-4-yl),thiazolidinyl (e.g. thiazolidin-2-yl, thiazolidin-3-yl,thiazolidin-4-yl), isothiazolidinyl, piperidinyl (e.g. piperidin-1-yl,piperidin-2-yl, piperidin-3-yl, piperidin-4-yl), homopiperidinyl (e.g.homopiperidin-1-yl, homopiperidin-2-yl, homopiperidin-3-yl,homopiperidin-4-yl), piperazinyl (e.g. piperazin-1-yl, piperazin-2-yl),morpholinyl (e.g. morpholin-2-yl, morpholin-3-yl, morpholin-4-yl),thiomorpholinyl (e.g. thiomorpholin-2-yl, thiomorpholin-3-yl,thiomorpholin-4-yl), 1-oxo-thiomorpholinyl, 1,1-dioxothiomorpholinyl,tetrahydrofuranyl (e.g. tetrahydrofuran-2-yl, tetrahydrofuran-3-yl),tetrahydrothienyl, tetrahydro-1,1-dioxothienyl, tetrahydropyranyl (e.g.2-tetrahydropyranyl), tetrahydrothiopyranyl (e.g.2-tetrahydrothiopyranyl), 1,4-dioxanyl, 1,3-dioxanyl, octahydroindolyl(e.g. octahydroindol-1-yl, octahydroindol-2-yl, octahydroindol-3-yl,octahydroindol-5-yl), decahydroquinolinyl (e.g. decahydroquinolin-1-yl,decahydroquinolin-2-yl, decahydroquinolin-3-yl, decahydroquinolin-4-yl,decahydroquinolin-6-yl), decahydroquinoxalinyl (e.g.decahydroquinoxalin-1-yl, decahydroquinoxalin-2-yl,decahydroquinoxalin-6-yl), 3-azabicyclo[3.2.2]nonyl,2-azabicyclo[2.2.1]heptyl, 3-azabicyclo[3.1.0]hexyl,2,5-diazabicyclo[2.2.1]heptyl, atropinyl, tropinyl, quinuclidinyl,1,4-diazabicyclo[2.2.2]octanyl, 1,4-dioxaspiro[4.5]decanyl (e.g.1,4-dioxaspiro[4.5]decan-2-yl, 1,4-dioxaspiro[4.5]decan-7-yl),1,4-dioxa-8-azaspiro[4.5]decanyl (e.g.1,4-dioxa-8-azaspiro[4.5]decan-2-yl,1,4-dioxa-8-azaspiro[4.5]decan-8-yl), 8-azaspiro[4.5]decanyl (e.g.8-azaspiro[4.5]decan-1-yl, 8-azaspiro[4.5]decan-8-yl),2-azaspiro[5.5]undecanyl (e.g. 2-azaspiro[5.5]undecan-2-yl),2,8-diazaspiro[4.5]decanyl (e.g. 2,8-diazaspiro[4.5]decan-2-yl,2,8-diazaspiro[4.5]decan-8-yl), 2,8-diazaspiro[5.5]undecanyl (e.g.2,8-diazaspiro[5.5]undecan-2-yl), 1,3,8-triazaspiro[4.5]decanyl (e.g.1,3,8-triazaspiro[4.5]decan-1-yl, 1,3,8-triazaspiro[4.5]decan-3-yl, and1,3,8-triazaspiro[4.5]decan-8-yl).

Preferred examples of “heterocycle” are pyrrolidinyl, pyrrolinyl,tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl,dihydrothiophenyl, imidzolidinyl, imidazolinyl, pyrazolidinyl,pyrazolinyl, oxazolidinyl, oxazoline, isoxazolidinyl, isoxazoline,thioxazolidinyl, thioxazoline, isothioxazolidinyl, isothioxazoline,triazolidinyl, triazolinyl, tetrazolidinyl, tetrazolinyl,tetrahydropyranyl, dihydropyranyl, pyran, piperidinyl, piperazinyl,homopiperazinyl, morpholinyl. Preferred heterocycle groups arepiperidinyl and morpholinyl.

“Therapeutically effective amount” is intended to include an amount of acompound of the present invention that is effective when administeredalone or in combination to activate glucokinase.

“Treating” or “treatment” cover the treatment of a disease-state in amammal, particularly in a human, and include: (a) preventing thedisease-state from occurring in a mammal, in particular, when suchmammal is predisposed to the disease-state but has not yet beendiagnosed as having it; (b) inhibiting the disease-state, e.g.,arresting or slowing its development; and/or (c) relieving thedisease-state, e.g., causing regression of the disease state itself orsome symptom of the disease state.

Pharmaceutically acceptable include pharmaceutically acceptable acidaddition salts, pharmaceutically acceptable base addition salts,pharmaceutically acceptable metal salts, ammonium salts, and alkylatedammonium salts. Acid addition salts include salts of inorganic acids aswell as organic acids. Representative examples of suitable inorganicacids include hydrochloric, hydrobromic, hydroiodic, phosphoric,sulfuric, and nitric acids. Representative examples of suitable organicacids include formic, acetic, trichloroacetic, trifluoroacetic,propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic,malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic,methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic,bismethylene salicylic, ethanedisulfonic, gluconic, citraconic,aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic,benzenesulfonic, p-toluenesulfonic acids, sulphates, nitrates,phosphates, perchlorates, borates, acetates, benzoates,hydroxynaphthoates, glycerophosphates, and ketoglutarates. Furtherexamples of pharmaceutically acceptable inorganic or organic acidaddition salts include the pharmaceutically acceptable salts listed inJ. Pharm. Sci. 1977, 66, 2, which is incorporated herein by reference.Examples of metal salts include lithium, sodium, potassium, magnesium,zinc, and calcium salts. Examples of amines and organic amines includeammonium, methylamine, dimethylamine, trimethylamine, ethylamine,diethylamine, propylamine, butylamine, tetramethylamine, ethanolamine,diethanolamine, triethanolamine, meglumine, ethylenediamine, choline,N,N′-dibenzylethylenediamine, N-benzylphenylethylamine,N-methyl-D-glucamine, and guanidine. Examples of cationic amino acidsinclude lysine, arginine, and histidine.

The pharmaceutically acceptable salts are prepared by reacting thecompound of formula I with 1 to 4 equivalents of a base such as sodiumhydroxide, sodium methoxide, sodium hydride, potassium t-butoxide,calcium hydroxide, and magnesium hydroxide, in solvents such as ether,THF, methanol, t-butanol, dioxane, isopropanol, ethanol etc. Mixture ofsolvents may be used. Organic bases such as lysine, arginine,diethanolamine, choline, guandine and their derivatives etc. may also beused. Alternatively, acid addition salts wherever applicable areprepared by treatment with acids such as hydrochloric acid, hydrobromicacid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulphonicacid, methanesulfonic acid, acetic acid, citric acid, maleic acidsalicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid,succinic acid, benzoic acid, benzenesulfonic acid, and tartaric acid insolvents such as ethyl acetate, ether, alcohols, acetone, THF, dioxaneetc. Mixture of solvents may also be used.

The stereoisomers of the compounds forming part of this invention may beprepared by using reactants in their single enantiomeric form in theprocess wherever possible or by conducting the reaction in the presenceof reagents or catalysts in their single enantiomer form or by resolvingthe mixture of stereoisomers by conventional methods. Some of thepreferred methods include use of microbial resolution, enzymaticresolution, resolving the diastereomeric salts formed with chiral acidssuch as mandelic acid, camphorsulfonic acid, tartaric acid, and lacticacid wherever applicable or chiral bases such as brucine, (R)- or(S)-phenylethylamine, cinchona alkaloids and their derivatives. Commonlyused methods are compiled by Jaques et al in “Enantiomers, Racemates andResolution” (Wiley Interscience, 1981). More specifically a compound ofthe present invention may be converted to a 1:1 mixture ofdiastereomeric amides by treating with chiral amines, aminoacids,aminoalcohols derived from aminoacids; conventional reaction conditionsmay be employed to convert acid into an amide; the diastereomers may beseparated either by fractional crystallization or chromatography and thestereoisomers of compound of formula I may be prepared by hydrolysingthe pure diastereomeric amide.

The invention also encompasses prodrugs of the present compounds, whichon administration undergo chemical conversion by metabolic processesbefore becoming active pharmacological substances. In general, suchprodrugs will be functional derivatives of the present compounds, whichare readily convertible in vivo into a compound of the presentinvention. Conventional procedures for the selection and preparation ofsuitable prodrug derivatives are described, for example, in “Design ofProdrugs”, ed. H. Bundgaard, Elsevier, 1985.

This invention will be better understood from the following examples,which are for purposes of illustration and are not intended to limit theinvention defined in the claims which follow thereafter.

EXAMPLES

All reactions involving air-sensitive reagents were performed undernitrogen using syringe-septum cap techniques. The glassware was dried byheating with a heat-gun. MgSO₄ was used to dry solutions. Solvents wereremoved in vacuo by rotary evaporation. Melting points were recorded ona Büchi 535. Bruker AMX 400 and Bruker DRX 300 instruments were used torecord ¹H NMR spectra at 400 and 300 MHz, respectively, withtetramethylsilane (TMS) as internal standard. Coupling constants (J) aregiven in Hz.

Materials

Test compounds were synthesized or when commercially available they werepurchased from Aldrich, Specs, Maybridge, or Bionet. For the synthesizedcompounds, the procedure for synthesis and measured characteristics ofthe compound are stated in the example. All compounds for which nosynthesis procedure is stated in the examples are commercially availableand have been purchased or were prepared by standard methods describedin the literature.

A general procedure may be as follows:

The synthetic intermediate of formula I with R1=H, R2=Br and acarboxylic ester group e.g.[4-(3-Bromo-5-hydroxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acidethyl acetate can be converted via a classical Mitsunobu reaction or areaction can be performed between the phenol and an alkyl halides (or analkyle mesylate, triflate, tosylate or alike) to a new intermediate offormula I where X1-R1 forms a ether or thioether group and R═Br. The newintermediate can be converted via a classical Sonogashira, Heck orSuzuki coupling protocol to a new intermediate where R2 is —C≡C—R^(2a),—CH═CH—R^(2a) or a substituted or non substituted aryl or heteroaryl. Itis also possible to perform the reaction in the opposite way by firstperforming the Sonogashira, Heck or Suzuki coupling followed by theether forming reaction as described above. The claimed compounds canalso be performed as described for[4-(3-Bromo-5-cyclopropylmethoxy-phenylsulfanyl)-2-methyl-phenoxy]-aceticacid ethyl ester by condensing e.g.1,3-dibromo-5-cyclopropylmethoxy-benzene or another substituteddibromophenyle ether with (4-Mercapto-2-methyl-phenoxy)-acetic acidethyl ester or another substituted mercaptobenzene. The intermediatesformed can be converted to the claimed compounds by a classical esterhydrolyses reaction from the respective esters of I (scheme 1-3).

General Procedure (A)

HPLC Systems

HPLC Method A

The RP-purification was performed on a Gilson system (4 Gilson 306pumps, Gilson 155 detector, Gilson reodyne manual injection, Gilson 811Cmixer and a Gilson 202 fraction collector) using a Phenomenex RPsynergi-MAX column (3 μm, 30 mm×250 mm) with gradient elution, 5% to100% solvent B (acetonitrile) in solvent A (water) within 40 min, 60mL/min, detection at 210 nm, room temperature. The pooled fractions wereeither evaporated to dryness in vacuo, or evaporated in vacuo until theMeCN is removed, and then frozen and freeze dried.

HPLC Method B

The RP-purification was performed on a Gilson system (3 Gilson 306pumps, Gilson 170 DAD detector and a Gilson 215 liquid-handler) using aWaters X-terra RP (10 μm, 30 mm×150 mm) with gradient elution, 5% to 95%solvent B (0.05% TFA in acetonitrile) in solvent A (0.05% TFA in water)within 15 min, 40 mL/min, detection at 210 nm, room temperature. Thepooled fractions were either evaporated to dryness in vacuo orevaporated in vacuo until the MeCN is removed and then frozen and freezedried.

HPLC-MS (System 1)

The RP-analysis was performed on an Agilent HPLC system (1100 degasser,1100 pump, 1100 injector and a 1100 DAD) fitted with an Agilent MSdetector system Model VL (MW 0-1000) and a S.E.D.E.R.E Model Sedex 55ELS detector system using a Waters X-terra MS C18 column (5 μm, 3.0mm×50 mm) with gradient elution, 5% to 95% solvent B (0.05% TFA inacetonitrile) in solvent A (0.05% TFA in water) within 3 min, 2.7mL/min.

Thin layer chromatography was performed on Merck DC-Alufolien, silicagel 60 F₂₅₄ and components were visualized by UV₂₅₄. Flashchromatography was performed using silica gel Merck 60 size 0.04-0-063mm and a Quad 12/25 flash system.

3,5-dibromophenol was prepared as described by Yang, et al., SynthCommun; 2003, 33, 19, 3317-3326.

Intermediates[4-(3-Bromo-5-hydroxy-benzylsulfanyl)-2-methyl-phenoxy]-acetic acidethyl ester

Step A: tert-Butyl-(3,5-dibromo-phenoxy)-dimethyl-silane

3,5-Dibromophenol (59.6 mmol; 15 g) and imidazole (65.5 mmol; 4.5 g)were dissolved in dichloromethane (150 mL) andtert-butyl-dimethylsilylchloride (65.5 mmol; 9.9 g) was added. Thereaction mixture was stirred at room temperature for 16 hours, dilutedwith diethyl ether, and filtered. The organic solution was washed withsaturated ammonium chloride, saturated sodium hydrogen carbonate, andwater and dried and evaporated to dryness. Yield: 22 g. HPLC-MS: m/z:366.9 (M+); Rt: 3.09 min.

Step B: 3-Bromo-5-(tert-butyl-dimethyl-silanyloxy)-benzaldehyde

tert-Butyl-(3,5-dibromo-phenoxy)-dimethyl-silane (22 g; 60.08 mmol) wasdissolved in THF (200 mL) in a dried reaction flask under an atmosphereof nitrogen. The mixture was cooled to −78° C. and n-BuLi (1.6 N inhexane; 41.25 mL; 66.09 mmol) was added while the temperature was keptbetween −60 and −78° C. The mixture was stirred for 15 min. and DMF(4.83 g; 66.08 mmol) was added. The reaction mixture was stirred for 1 hand methanol (5 mL) followed by saturated ammonium chloride was added.Etyl acetate (200 mL) was added and the organic phase was separated fromthe aqueous phase. The organic phase was washed with water, dried, andevaporated to dryness. The crude product was purified by flashchromatography (heptane:dichloromethane (1:1). Yield 7 g. HPLC-MS: m/z:317.0 (M+1); Rt: 2.7 min.

Step C: [3-Bromo-5-(tert-butyl-dimethyl-silanyloxy)-phenyl]-methanol

3-Bromo-5-(tert-butyl-dimethyl-silanyloxy)-benzaldehyde (7 g, 22.2 mmol)was dissolved in THF and sodium borohydride (0.92 g; 24.4 mmol) wasadded. The reaction mixture was stirred at room temperature for 2 h andwater was added, and the reaction mixture was partly evaporated to stripoff THF. Ethyl acetate was added and the phases separated. The organicphase was washed with water, dried, and evaporated to dryness. Yield:6.4 g; HPLC-MS: m/z: 317.0 (M+); Rt: 2.37 min.

Step D:{4-[3-Bromo-5-(tert-butyl-dimethyl-silanyloxy)-benzylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester

[3-Bromo-5-(tert-butyl-dimethyl-silanyloxy)-phenyl]-methanol (6.4 g;20.17 mmol) and (4-mercapto-2-methyl-phenoxy)-acetic acid ethyl ester(5.02 g; 22.19 mmol) were dissolved in THF (200 mL). Tributylphosphine(8.15 g; 40.34 mmol) and 1,1′-(azodicarbonyl)dipiperidine (10.17 g;40.34 mmol) were added, and the reaction mixture was stirred for 14 h atroom temperature. Water and ethyl acetate were added to the reactionmixture. The phases were separated. The organic phase was washed withwater, dried, and evaporated. The crude product was purified by flashchromatography (heptane:dichloromethane (1:1)). Yield: 8 g; 80%.HPLC-MS: m/z: 527.0 (M+1); Rt: 3.10 min.

Step E: [4-(3-Bromo-5-hydroxy-benzylsulfanyl)-2-methyl-phenoxy]-aceticacid ethyl ester

{4-[3-Bromo-5-(tert-butyl-dimethyl-silanyloxy)-benzylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester 7 g, 13.3 mmol) was dissolved in THF under anatmosphere of nitrogen. Tetrabutylammonium fluoride 1 N in THF (15 mL)was added, and the reaction mixture was stirred at 60° C. for 2 h.Saturated sodium carbonate and water were added together with ethylacetate, and the organic phase was separated. The organic phase waswashed with water, dried, and evaporated to dryness. Yield: 3.2 g.HPLC-MS: m/z: 435.4 (M+Na); Rt: 2.22 min.

[4-(3-Bromo-5-hydroxy-phenylsulfanyl)-2-chloro-phenoxy]-acetic acidethyl acetate

(2-Chloro-4-mercapto-phenoxy)-acetic acid ethyl ester (3 g; 12.16 mmol),dibromophenol (3.67 g; 14.59 mmol),tris(dibenzylideneacetone)dipalladium (0) (0.45 g; 0.49 mmol), and1,1′-bis-(diphenylphosphineo)ferrocenE (0.40 g; 0.73 mmol) were added toa dry reaction flask under an atmosphere of nitrogen. Triethylamine(6.74 mL, 48.64 mmol) and NMP (10 mL) were added, and the reactionmixture was stirred in a microwave oven for 1 h at 100° C. The reactionmixture was extracted with ethyl acetate, and the ethyl acetate phasewas washed twice with a 5% aqueous citric acid solution. The organicphase was dried and evaporated in vacuo. The crude reaction product waspurified by flash chromatography (dichloromethane→dichlormethane:ethylacetate (1:1)). Yield 1.8 g. HPLC-MS: m/z: 441.2 (M+Na); Rt: 2.34 min.

[4-(3-Bromo-5-hydroxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acidethyl acetate

(2-Methyl-4-mercapto-phenoxy)-acetic acid ethyl ester (6 g; 26.51 mmol),dibromophenol (8.68 g; 34.47 mmol),tris(dibenzylideneacetone)dipalladium (0) (0.97 g; 1.06 mmol), and1,1′-bis-(diphenylphosphineo)ferrocene (0.88 g; 1.59 mmol) were added toa dry reaction flask under an atmosphere of nitrogen. Triethylamine(10.73 mL, 106 mmol) and NMP (20 mL) were added, and the reactionmixture was stirred in a microwave oven for 1 h at 105° C. A 5% aqueouscitric acid solution (150 mL) was added to the reaction mixture, whichwas extracted with ethyl acetate (4×100 mL). The pooled organic phaseswere washed twice with water (30 mL), dried and evaporated in vacuo. Thecrude reaction product was purified by flash chromatography(heptane:ethyl acetate (10:1→7:3). Yield 6.5 g. HPLC-MS: m/z: 397.3(M+); Rt: 2.33 min.

{4-[3-Bromo-5-(3-morpholin-4-yl-propoxy)-phenylsulfanyl]-2-chloro-phenoxy}-aceticacid ethyl ester

[4-(3-Bromo-5-hydroxy-phenylsulfanyl)-2-chloro-phenoxy]-acetic acidethyl acetate (1.7 g; 4.07 mmol), N-(3-hydroxypropyl)morpholine (0.59 g;4.07 mmol) and tributylphosphine (1.8 g; 7.33 mmol) were dissolved inTHF (100 mL) in a dried reaction flask under an atmosphere of nitrogen.1,1′-(Azodicarbonyl)dipiperidine (1.85 g; 7.33 mmol) dissolved in THF(50 mL) was added to the reaction mixture, which was stirred at roomtemperature for 16 h. The reaction mixture was evaporated to dryness andpurified by flash chromatography (ethyl acetate:heptane). Yield: 1.1 g.HPLC-MS: m/z: 544.0 (M+); Rt: 1.78 min.

{2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-hydroxy-phenylsulfanyl]-phenoxy}-aceticacid ethyl ester

[4-(3-Bromo-5-hydroxy-phenylsulfanyl)-2-chloro-phenoxy]-acetic acidethyl acetate (1.1 g; 2.63 mmol), 4-chlorophenylacetylene (1.08 g; 7.9mmol), bis(triphenylphosphine)-palladium (II) chloride (0.15 g; 0.21mmol) and copper iodide (0.03 g; 0.16 mmol) were dissolved in a mixtureof triethylamine (5 mL) and DMF (5 mL) under an atmosphere of nitrogen.The reaction mixture was reacted in a microwave oven at 100° C. for 1 h.The reaction mixture was evaporated to dryness and portioned between 5%aqueous citric acid and ethyl acetate. The organic phase was dried andevaporated to dryness. The crude product was purified by flashchromatography (ethyl acetate:heptane 1:3). Yield: 1.1 g. HPLC-MS: m/z:473.3 (M+); Rt: 2.76 min.

[4-(3-hydroxy-5-phenylethynyl-phenylsulfanyl)-2-methyl-phenoxy]-aceticacid ethyl ester

[4-(3-Bromo-5-hydroxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acidethyl acetate (3 g; 7.55 mmol), 3-phenyl-1-propyn (2.63 g; 22.65 mmol),bis(triphenylphosphine)palladium (II) chloride (0.42 g; 0.60 mmol) andcopper iodide (0.086 g; 0.45 mmol) were dissolved in a mixture oftriethylamine (3 mL) and DMF (6 mL) under an atmosphere of nitrogen. Thereaction mixture was reacted in a microwave oven at 100° C. for 11 h.The reaction mixture was evaporated to dryness, and portioned between 5%aqueous citric acid and ethyl acetate. The organic phase was dried andevaporated to dryness. The crude product was purified by preparativeHPLC method A. Yield: 1.4 g. HPLC-MS: m/z: 433.3 (M+); Rt: min.

[4-(3-Hydroxy-5-phenylethynyl-phenylsulfanyl)-2-methyl-phenoxy]-aceticacid ethyl ester

[4-(3-Bromo-5-hydroxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acidethyl acetate (2.3 g; 5.79 mmol), phenylacetylene (1.9 mL; 17.4 mmol),bis(triphenylphosphine)palladium (II) chloride (0.33 g; 0.46 mmol) andcopper iodide (0.07 g; 0.35 mmol) were dissolved in a mixture oftriethylamine (7 mL) and DMF (8 mL) under an atmosphere of nitrogen. Thereaction mixture was reacted in a microwave oven at 100° C. for 1 h. Thereaction mixture was evaporated to dryness, and 5% aqueous citric acidand ethyl acetate was added. The organic phase was separated, dried andevaporated to dryness. The crude product was purified by flashchromatography (ethyl acetate:heptane 1:10->1:3). Yield: 1.2 g. HPLC-MS:m/z: 419 (M+); Rt: 2.52 min.

{4-[3-Hydroxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester

[4-(3-Bromo-5-hydroxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acidethyl acetate (3 g; 7.55 mmol), 4-prop-2-ynyl-morpholine (2.8 g; 22.65mmol), bis(triphenylphosphine)-palladium (II) chloride (0.42 g; 0.60mmol) and copper iodide (0.09 g; 0.45 mmol) were dissolved in a mixtureof triethylamine (7 mL) and DMF (8 mL) under an atmosphere of nitrogen.The reaction mixture was reacted in a microwave oven at 100° C. for 1.5h. The reaction mixture was purified by preparative HPLC (method A).Yield: 1.4 g. HPLC-MS: m/z: 442.4 (M+); Rt: 1.54 min.

{4-[3-Hydroxy-5-(3-morpholin-4-yl-prop-1-ynyl)-benzylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester

[4-(3-Bromo-5-hydroxy-benzylsulfanyl)-2-methyl-phenoxy]-acetic acidethyl ester (2.3 g; 5.6 mmol), 4-prop-2-ynyl-morpholine (2.1 g; 16.8mmol), bis(triphenylphosphine)palladium (II) chloride (0.31 g; 0.45mmol) and copper iodide (0.06 g; 0.34 mmol) were dissolved in a mixtureof triethylamine (5 mL) and DMF (10 mL) under an atmosphere of nitrogen.The reaction mixture was reacted in a microwave oven at 100° C. for 1 h.The reaction mixture was purified by preparative HPLC (method A). Yield:0.9 g. HPLC-MS: m/z: 456.1 (M+); Rt: 1.53 min.

{4-[3-Hydroxy-5-(3-phenyl-prop-1-ynyl)-benzylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester

[4-(3-Bromo-5-hydroxy-benzylsulfanyl)-2-methyl-phenoxy]-acetic acidethyl ester (2 g; 4.9 mmol), 3-phenyl-1-propyn (1.7 g; 14.6 mmol),bis(triphenylphosphine)palladium (II) chloride (0.27 g; 0.39 mmol) andcopper iodide (0.056 g; 0.29 mmol) were dissolved in a mixture oftriethylamine (5 mL) and DMF (10 mL) under an atmosphere of nitrogen.The reaction mixture was reacted in a microwave oven at 100° C. for 1 h.Further 3-phenyl-1-propyn (1.7 g; 14.6 mmol) was added and the reactionmixture was reacted in a microwave oven at 100° C. for further 1 h. Thereaction mixture was purified by preparative HPLC (method A). Yield: 0.8g. HPLC-MS: m/z: 434.6 (M+1); Rt: 2.43 min.

{4-[3-Bromo-5-cyclohexylmethoxy-phenylsulfanyl)-2-methyl-phenoxy]-aceticacid ethyl ester

[4-(3-Bromo-5-hydroxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acidethyl acetate ester (0.23 g; 0.58 mmol), cyclohexyl-methanol (80 μl;0.64 mmol) and tributylphosphine (0.21 mL; 0.87 mmol) were dissolved inTHF (10 mL) in a dried reaction flask under an atmosphere of nitrogen.1,1′-(Azodicarbonyl)dipiperidine (0.22 g; 0.87 mmol) dissolved in THF(10 mL) was added to the reaction mixture, which was stirred at roomtemperature for 2 days. The reaction mixture was filtered, evaporated todryness and purified by flash chromatography (ethyl acetate:heptane1:1). Yield: 100 mg. HPLC-MS: m/z: 493.4 (M)+; Rt: 3.17 min.

{4-[3-Bromo-5-cyclopentylmethoxy-phenylsulfanyl)-2-methyl-phenoxy]-aceticacid ethyl ester

1,3-Dibromo-5-cyclopentylmethoxy-benzene

3,5-Dibromophenol (5.0 g; 19.8 mmol), cyclopentane-methanol (2.0 g; 19.9mmol) and tributylphosphine (8.8 mL; 35.7 mmol) were dissolved in dryTHF (250 mL) in a dried reaction flask under an atmosphere of nitrogen.1,1′-(Azodicarbonyl)dipiperidine (9.01 g; 35.7 mmol) dissolved in dryTHF (150 mL) was added to the reaction mixture, which was stirred atroom temperature for 16 hours. The reaction mixture was filtered,evaporated to dryness and purified by flash chromatography(heptane→ethyl acetate:heptane 2:3). Yield: 5.68 g; 86%.

[4-(3-Bromo-5-cyclopentylmethoxy-phenylsulfanyl)-2-methyl-phenoxy]-aceticacid ethyl ester

1,3-Dibromo-5-cyclopentylmethoxy-benzene (2.9 g; 8.6 mmol),(4-Mercapto-2-methyl-phenoxy)-acetic acid ethyl ester (1.5 g; 6.6 mmol),tris(dibenzylideneacetone)dipalladium(0) (0.18 g, 0.20 mmol) and1,1′-bis(diphenylphosphino)-ferrocen (0.22 g; 0.40 mmol) was added to adried microwave flask under an atmosphere of nitrogene. The reactionflask was sealed and dry NMP (10 mL) and TEA (3.7 mL; 26.5 mmol) wasadded through the septum. The reaction flask was reacted in a microwaveoven at 140° C. for 1 h. Ethyl acetate (30 mL) and aqueous 5% citricacid (30 mL) was added to the reaction mixture and the phases wereseparated. The aqueous phase was extracted with ethyl acetate (30 mL×2)and the pooled organic phases were dried (MgSO₄) and evaporated todryness. The reaction mixture was purified by flash chromatography(heptane→heptane: ethyl acetate (9:1½). Yield: 1.45 g (46%). HPLC-MS:m/z: 479.8 (M)+; Rt: 3.18 min.

{4-[3-Bromo-5-isobutoxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acidethyl ester

{4-[3-Bromo-5-isobutoxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acidethyl ester was prepared as described for{4-[3-Bromo-5-cyclopentylmethoxy-phenylsulfanyl)-2-methyl-phenoxy]-aceticacid ethyl ester. Yield: 45%. HPLC-MS: m/z: 454.8 (M+H)+; Rt: 3.07 min.

(4-{3-Bromo-5-[2-(4-chloro-phenyl)-ethoxy]-phenylsulfanyl}-2-methyl-phenoxy)-aceticacid ethyl ester

(4-{3-Bromo-5-[2-(4-chloro-phenyl)-ethoxy]-phenylsulfanyl}-2-methyl-phenoxy)-aceticacid ethyl ester was prepared as described for{4-[3-Bromo-5-cyclopentylmethoxy-phenylsulfanyl)-2-methyl-phenoxy]-aceticacid ethyl ester. Yield: 25%. HPLC-MS: m/z: 537.1 (M+2); Rt: 3.11 min.

{4-[3-Bromo-5-(2-ethyl-butoxy)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester

{4-[3-Bromo-5-(2-ethyl-butoxy)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester was prepared as described for{4-[3-Bromo-5-cyclopentylmethoxy-phenylsulfanyl)-2-methyl-phenoxy]-aceticacid ethyl ester. Yield: 63%. HPLC-MS: m/z: 481.0 (M)⁺; Rt: 3.20 min.

[4-(3-Bromo-5-cyclopentyloxy-phenylsulfanyl)-2-methyl-phenoxy]-aceticacid ethyl ester

[4-(3-Bromo-5-cyclopentyloxy-phenylsulfanyl)-2-methyl-phenoxy]-aceticacid ethyl ester was prepared as described for{4-[3-Bromo-5-cyclopentylmethoxy-phenylsulfanyl)-2-methyl-phenoxy]-aceticacid ethyl ester. Yield: 51%. HPLC-MS: m/z: 565.0 (M)⁺; Rt: 3.04 min.

{4-[3-Bromo-5-(4-methanesulfonyl-benzyloxy)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester

{4-[3-Bromo-5-(4-methanesulfonyl-benzyloxy)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester was prepared as described for{4-[3-Bromo-5-cyclopentylmethoxy-phenylsulfanyl)-2-methyl-phenoxy]-aceticacid ethyl ester. Yield: 9%. HPLC-MS: m/z: 565.2 (M)⁺; Rt: 2.58 min.

{4-[3-Bromo-5-(2-cyclohexyl-ethoxy)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester

{4-[3-Bromo-5-(2-cyclohexyl-ethoxy)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester was prepared as described for{4-[3-Bromo-5-cyclopentylmethoxy-phenylsulfanyl)-2-methyl-phenoxy]-aceticacid ethyl ester. Yield: 51%. HPLC-MS: m/z: 508.8 (M+H)+; Rt: 3.33 min.

{4-[3-Bromo-5-(3-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester

2-(3,5-Dibromo-phenoxy)-3-trifluoromethyl-pyridine

3,5-Dibromophenol (2.0 g; 7.9 mmol), 2-chloro-3-trifluoropyridine (1.4g; 7.9 mmol), potassium hydroxide (0.45 g; 7.9 mmol) and DMSO (40 mL)was added to a reaction flask under an atmosphere of nitrogen. Thereaction mixture was reacted at 110° C. for 6 h. The reaction mixturewas cooled to room temperature and ethyl acetate (30 ml) and water (120mL) was added. The organic phase was separated form the aqueous phaseand the aqueous phase was extracted with ethyl acetate (30 mL×4). Thecombined organic phases were dried, evaporated to dryness and purifiedby flash chromatography (heptane→ethyl acetate:heptane 1:8). Yield: 2.23g; 71%. HPLC-MS: m/z: 397.9 (M)+; Rt: 2.58 min.

{4-[3-Bromo-5-(3-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester

2-(3,5-Dibromo-phenoxy)-3-trifluoromethyl-pyridine (2.05 g; 5.17 mmol)and (4-Mercapto-2-methyl-phenoxy)-acetic acid ethyl ester (0.9 g; 4.0mmol) was condensed to give the title product applying the proceduredescribed for{4-[3-Bromo-5-cyclopentylmethoxy-phenylsulfanyl)-2-methyl-phenoxy]-aceticacid ethyl ester. The crude product was purified by flash chromatography(heptane→ethyl acetate:heptane 2:9). Yield 1.26 g (58%). HPLC-MS: m/z:544.3 (M+2); Rt: 2.77 min.

{4-[3-Bromo-5-(5-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester

2-(3,5-Dibromo-phenoxy)-5-trifluoromethyl-pyridine

The title product was prepared as described for2-(3,5-Dibromo-phenoxy)-3-trifluoro-methyl-pyridine Yield: 70%; HPLC-MS:m/z: 397.7 (M)+; Rt 2.60 min.

{4-[3-Bromo-5-(5-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester

2-(3,5-Dibromo-phenoxy)-5-trifluoromethyl-pyridine (2.5 g; 6.3 mmol) and(4-Mercapto-2-methyl-phenoxy)-acetic acid ethyl ester (1.1 g; 4.9 mmol)was condensed to give the title product applying the procedure describedfor{4-[3-Bromo-5-cyclopentylmethoxy-phenylsulfanyl)-2-methyl-phenoxy]-aceticacid ethyl ester. The crude product was purified by flash chromatography(heptane→ethyl acetate:heptane 2:9). Yield 1.4 g (53%). HPLC-MS: m/z:544.3 (M+2); Rt: 2.80 min.

{4-[3-Bromo-5-(3-trifluoromethyl-phenoxy)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester

1,3-Dibromo-5-(3-trifluoromethyl-phenoxy)-benzene

3,5-Dibromophenol (4.1 g; 16.2 mmol), 3-(trifluoromethyl)-phenylboronicacid (6.2 g; 32.4 mmol), Cu(II) acetate (2.9 g; 16.2 mmol), TEA (5.6 mL;40.5 mmol) and dichloromethane (150 mL) and molecular sieves (2 ml) wasadded to a reaction flask the reaction mixture was stirred for 7 days.Further 3-(trifluoromethyl)-phenylboronic acid (6.2 g; 32.4 mmol) wasadded and the reaction mixture stirred for 1 day. Further3-(trifluoromethyl)-phenylboronic acid (6.2 g; 32.4 mmol) and TEA (5.6mL; 40.5 mmol) was added and the reaction mixture stirred for 1 day. 5%Aqueous citric acid (150 mL) was added and the two phases wereseparated. The aqueous phase was extracted with dichloromethane (50mL×2) and the organic phases were pooled, dried and evaporated todryness. The crude product purified by flash chromatography(heptane→ethyl acetate:heptane 1:9). Yield: 1.86 g; HPLC-MS: m/z: 397.(M+H)+; Rt: 2.78 min.

{4-[3-Bromo-5-(3-trifluoromethyl-phenoxy)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester

1,3-Dibromo-5-(3-trifluoromethyl-phenoxy)-benzene (1.35 g; 3.4 mmol) and(4-Mercapto-2-methyl-phenoxy)-acetic acid ethyl ester (0.7 g; 3.1 mmol)was condensed to give the title product applying the procedure describedfor{4-[3-Bromo-5-cyclopentylmethoxy-phenylsulfanyl)-2-methyl-phenoxy]-aceticacid ethyl ester. The crude product was purified by preparative HPLC(Method A) followed by flash chromatography (dichloromethane:heptane3:7). Yield 0.5 g. HPLC-MS: m/z: 541.3 (M)+; Rt: 3.03 min.

[4-(3-Bromo-5-cyclopropylmethoxy-benzylsulfanyl)-2-methyl-phenoxy]-aceticacid ethyl ester

[4-(3-Bromo-5-hydroxy-benzylsulfanyl)-2-methyl-phenoxy]-acetic acidethyl ester (1.0 g; 2.43 mmol), cyclopropylcarbinol (175 mg; 2.43 mmol)and tributylphosphine (1.07 mL; 4.38 mmol) was dissolved in THF (100 mL)in a dried reaction flask under an atmosphere of nitrogen.1,1′-(Azodicarbonyl)dipiperidine (1.1 g; 4.38 mmol) dissolved in THF (20mL) was added to the reaction mixture, which was stirred at roomtemperature for 16 hours. The reaction mixture was filtered, evaporatedto dryness and purified by flash chromatography (ethyl acetate:heptane1:9→2:3). Yield: 980 mg; 86%; HPLC-MS: m/z: 465.0 (M)⁺; Rt: 2.74 min.

[4-(3-Bromo-5-cyclopropylmethoxy-phenylsulfanyl)-2-methyl-phenoxy]-aceticacid ethyl ester

Step A: 1,3-Dibromo-5-cyclopropylmethoxy-benzene

3,5-Dibromo-phenol (5 g; 19.9 mmol), cyclopropylcarbinol (1.4 g; 19.9mmol) and tributylphosphine (8.8 mL; 35.7 mmol) were dissolved in THF(500 mL) in a dried reaction flask under an atmosphere of nitrogen.1,1′-(Azodicarbonyl)dipiperidine (9.0 g; 35.7 mmol) dissolved in THF(100 mL) was added to the reaction mixture, which was stirred at roomtemperature for 16 hours. The reaction mixture was partly evaporated,filtered, evaporated to dryness and purified by flash chromatography(ethyl acetate:heptane 0:1→1:10). Yield: 5.45 g; 90%.

Step B:[4-(3-Bromo-5-cyclopropylmethoxy-phenylsulfanyl)-2-methyl-phenoxy]-aceticacid ethyl ester

1,3-Dibromo-5-cyclopropylmethoxy-benzene (5.27 g; 17.23 mmol),(4-Mercapto-2-methyl-phenoxy)-acetic acid ethyl ester (3 g; 13.26 mmol),tris(dibenzylideneacetone)dipalladium (0) (0.36 g; 0.40 mmol), and1,1′-bis-(diphenylphosphineo)ferrocene (0.44 g; 0.80 mmol) was added toa dry reaction flask under an atmosphere of nitrogen. Triethylamine(7.45 mL) and NMP (8 mL) was added, and the reaction mixture was stirredin a microwave oven for 1 h at 140° C. A 5% aqueous citric acid solution(150 mL) was added to the reaction mixture, which was extracted withethyl acetate (4×100 mL). The pooled organic phases were dried andevaporated in vacuo. The crude reaction product was purified by flashchromatography (heptane: ethyl acetate (20:1→7:3). Yield 2.8 g; 47%).HPLC-MS: m/z: 451.0 (M+); Rt: 2.85 min

[4-(3-Bromo-5-isobutoxy-phenylsulfanyl)-2,5-dimethyl-phenoxy]-aceticacid ethyl ester

Step A1: 1,3-Dibromo-5-isobutoxy-benzene

Potassium hydroxide (15.9 g; 284 mmol) was dissolved in water (300 ml)and 3,5-dibromo-phenol (47 g; 188.5 mmol) was added. Benzyltributylammoniumchloride (17.7 g; 56.8 mmol) and toluene (200 ml) wasadded and the reaction mixture was heated to 85° C. Bromoethylpropan(32.3 g; 325.7 mmol) was added over 5 hours and the reaction mixture wasstirred at 85° C. for additional 16 h. The reaction mixture was cooledto room temperature and the phases were separated. Toluene (100 ml) wasadded to the organic phase which was washed with 0.2 N aqueous HCl (200ml×2) and water (200 ml×2). The organic phase was evaporated to give thecrude product which was purified by distillation (0.7.mm Hg; Bp: 98°C.); Yield: 43 g (colourless oil).

Step A2: (4-Mercapto-2,5-dimethyl-phenoxy)-acetic acid ethyl ester

(4-Mercapto-2,5-dimethyl-phenoxy)-acetic acid ethyl ester was preparedas described for 2,6-difluoro-4-mercapto-phenoxy)acetic acid methylester (compound 21) in Eur. J. Med. Chem., 1995, 30, 403 (Kawashima, M.S.) except that (4-chlorosulfonyl-2,5-dimethyl-phenoxy)acetic acid ethylester was reduced with 4 eq. of zn (dust) in a mixture of konc. sulfuricacid and ethanol at 80° C.

Step B:[4-(3-Bromo-5-isobutoxy-phenylsulfanyl)-2,5-dimethyl-phenoxy]-aceticacid ethyl ester

1,3-Dibromo-5-isobutoxy-benzene (1.66 g; 5.4 mmol),(4-Mercapto-2,5-dimethyl-phenoxy)-acetic acid ethyl ester (1.0 g; 4.1mmol), tris(dibenzylideneacetone)dipalladium (0) (0.11 g; 0.12 mmol),and 1,1′-bis-(diphenylphosphineo)ferrocene (0.14 g; 0.25 mmol) wereadded to a dry reaction flask under an atmosphere of nitrogen.Triethylamine (2.3 mL) and NMP (10 mL) was added, and the reactionmixture was stirred in a microwave oven for 1 h at 140° C. A 5% aqueouscitric acid solution (150 mL) was added to the reaction mixture, whichwas extracted with ethyl acetate (4×100 mL). The pooled organic phaseswere dried and evaporated in vacuo. The crude reaction product waspurified by flash chromatography (heptane: ethyl acetate (10:1→1:1).Yield: 1.3 g; 67%. HPLC-MS: m/z: 467.0 (M+); Rt: 3.10 min

[4-(3-Bromo-5-isobutoxy-phenoxy)-2-methyl-phenoxy]-acetic acid methylester

Step A: 3-Bromo-5-isobutoxy-phenylboronic acid

1,3-Dibromo-5-isobutoxy-benzene (1. g; 3.3 mmol) was dissolved in dryTHF (30 ml) in a dry reaction under stirring. The reaction mixture wascooled to −70° C. and n-BuLi (2M; 2.44 ml) was added. The reactionmixture was stirred for 15 min. and triisobutylborate (1.50 ml; 6.5mmol) was added at −70° C. The temperature was raised to −30° C. andstirred for 1½ hour followed by a temperature increase to roomtemperature. The reaction mixture was quenched with saturated aqueoussodium hydrogen carbonate (about 3 ml) and evaporated to dryness. Thecrude product was purified by prep HPLC (method B). Yield: 430 mg; 49%.HPLC-MS: m/z: 272.9 (M+); Rt: 2.08 min

Step B: [4-(3-Bromo-5-isobutoxy-phenoxy)-2-methyl-phenoxy]-acetic acidmethyl ester

(4-Hydroxy-2-methyl-phenoxy)-acetic acid methyl ester (215 mg; 1.1mmol), 3-Bromo-5-isobutoxy-phenylboronic acid (523.4; 1.9 mmol),copper(II) acetate (199 mg; 1.1 mmol), crushed molsieves (about 1 g) andtriethylamine (0.46 ml; 3.3 mmol) was dissolved in dichloromethane (40ml) and stirred over night. The reaction mixture was filtered throughcelite and evaporated to dryness. The crude product was purified bypreparative HPLC (method B). Yield: 300 mg; 65%. HPLC-MS: m/z: 423.5(M+); Rt: 2.71 min

Example 1{2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(3-piperidin-1-yl-propoxy)-phenylsulfanyl]-phenoxy}-aceticacid

Step A:{2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(3-piperidin-1-yl-propoxy)-phenylsulfanyl]-phenoxy}-aceticacid ethyl ester

[{2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-hydroxy-phenylsulfanyl]-phenoxy}-aceticacid ethyl ester (0.4 g; 0.85 mmol), 3-piperidin-1-yl-propan-1-ol (0.12g; 0.85 mmol) and tributylphosphine (0.37 mL; 1.5 mmol) were dissolvedin THF (50 mL) in a dried reaction flask under an atmosphere ofnitrogen. 1,1′-(Azodicarbonyl)dipiperidine (0.38 g; 1.5 mmol) dissolvedin THF (25 mL) was added to the reaction mixture, which was stirred atroom temperature for 16 h. The reaction mixture was evaporated todryness and 5% aqueous citric acid and ethyl acetate was added. Theorganic phase was separated, dried, evaporated to dryness, and purifiedby prep HPLC (method A). Yield: 275 mg. HPLC-MS: m/z: 598.0 (M+); Rt:2.3 min.

Step B:{2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(3-piperidin-1-yl-propoxy)-phenylsulfanyl]-phenoxy}-aceticacid

{2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(3-piperidin-1-yl-propoxy)-phenylsulfanyl]-phenoxy}-aceticacid ethyl ester (275 mg; 0.46 mmol) was dissolved in ethanol (15 mL)and aqueous 1N sodium hydroxide (3 mL) was added. The reaction mixturewas stirred for 16 h, acidified with 5% aqueous citric acid, andextracted with ethyl acetate. The organic phase was dried and evaporatedto dryness. Yield: 200 mg. HPLC-MS: m/z: 570.0 (M+); Rt: 2.07 min.

Example 2{2-Methyl-4-[3-(3-morpholin-4-yl-propoxy)-5-phenylethynyl-phenylsulfanyl]-phenoxy}-aceticacid

Step A:{2-Methyl-4-[3-(3-morpholin-4-yl-propoxy)-5-phenylethynyl-phenylsulfanyl]-phenoxy}-aceticacid ethyl ester

[4-(3-Hydroxy-5-phenylethynyl-phenylsulfanyl)-2-methyl-phenoxy]-aceticacid ethyl ester (0.25 g; 0.60 mmol), 3-morpholin-4-yl-propan-1-ol (0.12g; 0.84 mmol) and tributylphosphine (0.27 mL; 1.08 mmol) were dissolvedin THF (20 mL) in a dried reaction flask under an atmosphere ofnitrogen. 1,1′-(Azodicarbonyl)dipiperidine (0.27 g; 1.08 mmol) dissolvedin THF (10 mL) was added to the reaction mixture, which was stirred atroom temperature for 16 h. The reaction mixture was evaporated todryness, acetonitrile added, and the mixture filtered. The solution waspurified by prep HPLC (method A). Yield: 150 mg. HPLC-MS: m/z: 546.6(M+H); Rt: 2.08 min.

Step B:{2-Methyl-4-[3-(3-morpholin-4-yl-propoxy)-5-phenylethynyl-phenylsulfanyl]-phenoxy}-aceticacid

{2-Methyl-4-[3-(3-morpholin-4-yl-propoxy)-5-phenylethynyl-phenylsulfanyl]-phenoxy}-aceticacid ethyl ester (150 mg; 0.28 mmol) was dissolved in ethanol (15 mL),and aqueous 1N sodium hydroxide (3 mL) was added. The reaction mixturewas stirred for 16 h, acidified with 1N aqueous hydrochloric acid, andextracted with ethyl acetate. The organic phase was dried and evaporatedto dryness. Yield: 110 mg. HPLC-MS: m/z: 518.1 (M+H); Rt: 1.86 min.

Example 3{2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(3-morpholin-4-yl-propoxy)-phenyl-sulfanyl]-phenoxy}-aceticacid

Step A:{2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(3-morpholin-4-yl-propoxy)-phenylsulfanyl]-phenoxy}-aceticacid ethyl ester

[{2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-hydroxy-phenylsulfanyl]-phenoxy}-aceticacid ethyl ester (293 mg; 0.62 mmol) was dissolved in THF (15 mL) in adried reaction flask under an atmosphere of nitrogen.3-morpholin-4-yl-propan-1-ol (75 mg; 0.52 mmol) and tributyl-phosphine(0.23 mL; 0.93 mmol) was added followed by1,1′-(Azodicarbonyl)dipiperidine (0.38 g; 1.5 mmol) dissolved in THF (10mL). The reaction mixture was stirred at room temperature for 16 h,filtered and evaporated in vacuo. The crude product was purified byprep. HPLC (method B). Yield: 200 mg. HPLC-MS: m/z: 600.4 (M+); Rt: 2.2min.

Step B:{2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(3-morpholin-4-yl-propoxy)-phenylsulfanyl]-phenoxy}-aceticacid

{2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(3-morpholin-4-yl-propoxy)-phenyl-sulfanyl]-phenoxy}-aceticacid ethyl ester (200 mg; 0.33 mmol) was dissolved in ethanol (10 mL),and aqueous 1N sodium hydroxide (3 mL) was added. The reaction mixturewas stirred for 16 h, acidified with 1N aqueous hydrochloric acid, andextracted with ethyl acetate. The organic phase was dried, evaporated todryness, and purified by prep. HPLC (method A). Yield: 46 mg. HPLC-MS:m/z: 572.3 (M+); Rt: 2.03 min.

Example 4{2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(4-morpholin-4-ylmethyl-benzyloxy)-phenylsulfanyl]-phenoxy}-aceticacid

Step A:{2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(4-morpholin-4-ylmethyl-benzyloxy)-phenylsulfanyl]-phenoxy}-aceticacid ethyl ester

{2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-hydroxy-phenylsulfanyl]-phenoxy}-aceticacid ethyl ester (274 mg; 0.58 mmol) was dissolved in THF (15 mL) in adried reaction flask under an atmosphere of nitrogen.(4-Morpholin-4-ylmethyl-phenyl)-methanol (100 mg; 0.48 mmol) andtributylphosphine (0.21 mL; 0.87 mmol) was added followed by1,1′-(Azodicarbonyl)dipiperidine (0.22 g; 0.87 mmol) dissolved in THF(10 mL). The reaction mixture was stirred at room temperature for 5 h,filtered and evaporated in vacuo. The crude product was purified byprep. HPLC (method A). Yield: 250 mg. HPLC-MS: m/z: 663.0 (M+H); Rt:2.47 min.

Step B:{2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(4-morpholin-4-ylmethyl-benzyloxy)-phenylsulfanyl]-phenoxy}-aceticacid

{2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(4-morpholin-4-ylmethyl-benzyloxy)-phenylsulfanyl]-phenoxy}-aceticacid ethyl ester (250 mg; 0.38 mmol) was dissolved in ethanol (10 mL),and aqueous 1N sodium hydroxide (5 mL) was added. The reaction mixturewas stirred for 16 h, acidified with 1N aqueous hydrochloric acid, andextracted with ethyl acetate. The organic phase was dried, evaporated todryness and purified by prep. HPLC (method A). Yield: 32 mg. HPLC-MS:m/z: 634.5 (M+); Rt: 2.21 min.

Example 5{2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(1-methyl-piperidin-4-ylmethoxy)-phenylsulfanyl]-phenoxy}-aceticacid

Step A:{2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(1-methyl-piperidin-4-ylmethoxy)-phenylsulfanyl]-phenoxy}-aceticacid ethyl ester

{2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-hydroxyl-phenylsulfanyl]-phenoxy}-aceticacid ethyl ester (274 mg; 0.58 mmol) was dissolved in THF (15 mL) in adried reaction flask under an atmosphere of nitrogen.1-(Methyl-piperidin-4-yl)-methanol (100 mg; 0.48 mmol) andtributylphosphine (0.21 mL; 0.87 mmol) were added followed by1,1′-(Azodicarbonyl)dipiperidine (0.22 g; 0.87 mmol) dissolved in THF(10 mL). The reaction mixture was stirred at room temperature for 5 h,filtered, and evaporated in vacuo. The crude product was purified byprep. HPLC (method B). Yield: 250 mg. HPLC-MS: m/z: 663.0 (M+H); Rt:2.47 min.

Step B:{2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(1-methyl-piperidin-4-ylmethoxy)phenylsulfanyl]-phenoxy}-aceticacid

{2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(1-methyl-piperidin-4-ylmethoxy)phenylsulfanyl]-phenoxy}-aceticacid ethyl ester (60 mg; 0.10 mmol) was dissolved in ethanol (7 mL), andaqueous 1N sodium hydroxide (3 mL) was added. The reaction mixture wasstirred for 16 h, acidified with 1N aqueous hydrochloric acid, andextracted with ethyl acetate. The organic phase was dried, evaporated todryness and purified by prep. HPLC (method B). Yield: 20 mg. HPLC-MS:m/z: 556.5 (M+); Rt: 2.10 min.

Example 6{2-Methyl-4-[3-(3-morpholin-4-yl-propoxy)-5-(3-phenyl-prop-1-ynyl)-phenylsulfanyl]-phenoxy}-aceticacid

Step A:{2-Methyl-4-[3-(3-morpholin-4-yl-propoxy)-5-(3-phenyl-prop-1-ynyl)-phenylsulfanyl]-phenoxy}-aceticacid ethyl ester

{4-[3-Hydroxy-5-(3-phenyl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester (200 mg; 0.46 mmol), 3-morpholin-4-yl-propan-1-ol (101mg; 0.69 mmol), tributylphosphine (0.28 mL; 1.39 mmol) and1,1′-(azodicarbonyl)dipiperidine (0.35 g; 1.39 mmol) were dissolved inTHF (15 mL) in a dried reaction flask under an atmosphere of nitrogen.After stirring for 1 h the reaction mixture was purified by prep. HPLC(method A). Yield: 200 mg. HPLC-MS: m/z: 560.5 (M+H); Rt: 2.07 min.

Step B:{2-Methyl-4-[3-(3-morpholin-4-yl-propoxy)-5-(3-phenyl-prop-1-ynyl)-phenylsulfanyl]-phenoxy}-aceticacid

{2-Methyl-4-[3-(3-morpholin-4-yl-propoxy)-5-(3-phenyl-prop-1-ynyl)-phenylsulfanyl]-phenoxy}-aceticacid ethyl ester (200 mg; 0.36 mmol) was dissolved in ethanol (20 mL),and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixturewas stirred for 1 h, acidified with 1 N aqueous hydrochloric acid, andextracted with ethyl acetate. The organic phase was dried and evaporatedto dryness. Yield: 150 mg. HPLC-MS: m/z: 532.1 (M+); Rt: 1.87 min.

Example 7{4-[3-(4-Fluoro-benzyloxy)-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid

Step A:{4-[3-(4-Fluoro-benzyloxy)-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester

{4-[3-Hydroxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester (200 mg; 0.45 mmol), 4-fluorobenzylalcohol (85.7 mg;0.68 mmol), tributylphosphine (0.27 mL; 1.36 mmol) and1,1′-(azodicarbonyl)dipiperidine (0.34 g; 1.36 mmol) were dissolved inTHF (15 mL) in a dried reaction flask under an atmosphere of nitrogen.After stirring for 1 h the reaction mixture was purified by prep. HPLC(method A). Yield: 200 mg. HPLC-MS: m/z: 550.3 (M+H); Rt: 2.00 min.

Step B:{4-[3-(4-Fluoro-benzyloxy)-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid

{4-[3-(4-Fluoro-benzyloxy)-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester (200 mg; 0.36 mmol) was dissolved in ethanol (20 mL),and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixturewas stirred for 1 h, acidified with 1 N aqueous hydrochloric acid, andextracted with ethyl acetate. The organic phase was dried and evaporatedto dryness. Yield: 170 mg. HPLC-MS: m/z: 522.1 (M+); Rt: 1.77 min.

Example 8{4-[3-Cyclohexylmethoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid

Step A:{4-[3-Cyclohexylmethoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester

{4-[3-Hydroxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester (200 mg; 0.45 mmol), cyclohexylmethanol (77.6 mg; 0.68mmol), tributylphosphine (0.27 mL; 1.36 mmol) and1,1′-(azodicarbonyl)dipiperidine (0.34 g; 1.36 mmol) were dissolved inTHF (15 mL) in a dried reaction flask under an atmosphere of nitrogen.After stirring for 1 h the reaction mixture was purified by prep. HPLC(method A). Yield: 200 mg. HPLC-MS: m/z: 538.1 (M+H); Rt: 2.24 min.

Step B:{4-[3-Cyclohexylmethoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid

{4-[3-Cyclohexylmethoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester (200 mg; 0.37 mmol) was dissolved in ethanol (20 mL),and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixturewas stirred for 1 h, acidified with 1 N aqueous hydrochloric acid, andextracted with ethyl acetate. The organic phase was dried and evaporatedto dryness. Yield: 180 mg. HPLC-MS: m/z: 510.1 (M+); Rt: 1.98 min.

Example 9{4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid

Step A:{4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester

{4-[3-Hydroxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester (250 mg; 0.57 mmol), 2-methyl-propan-1-ol (0.078 mL;0.85 mmol) and tributylphosphine (0.31 mL; 1.25 mmol) were dissolved inTHF (15 mL) in a dried reaction flask under an atmosphere of nitrogen.1,1′-(Azodicarbonyl)dipiperidine (0.31 g; 1.25 mmol) was dissolved inTHF (10 mL) and added to the reaction mixture. After stirring for 16 hthe reaction mixture was evaporated to dryness and purified by prep.HPLC (method B). Yield: 200 mg. HPLC-MS: m/z: 498.1 (M+); Rt: 2.03 min

Step B:{4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid

{4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester (140 mg; 0.28 mmol) was dissolved in ethanol (15 mL),and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixturewas stirred for 1 h, acidified with 1 N aqueous hydrochloric acid, andextracted with ethyl acetate. The organic phase was dried and evaporatedto dryness. Yield: 130 mg. HPLC-MS: m/z: 470.0 (M+); Rt: 1.76 min.δ_(H)(400 MHz; CDCl₃) 1.00 (d, 6H), 1.98-2.09 (m, 1H), 2.27 (s, 3H),3.13-3.29 (m, 2H), 3.43-3.57 (m, 2H), 3.66 (d, 2H), 3.92-4.09 (m, 4H),4.12 (s, 2H), 4.71 (s, 2H), 6.55 (m, 1H), 6.71-6.75 (m, 2H), 6.79 (m,1H), 7.25-7.29 (m, 1H), 7.30 (m, 1H).

Example 10{4-[3-(4-Chloro-benzyloxy)-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid

Step A:{4-[3-(4-Chloro-benzyloxy)-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester

4-[3-Hydroxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester (250 mg; 0.57 mmol), 4-(chloro-phenyl)-methanol (0.12mg; 0.85 mmol) and tributylphosphine (0.31 mL; 1.25 mmol) were dissolvedin THF (15 mL) in a dried reaction flask under an atmosphere ofnitrogen. 1,1′-(Azodicarbonyl)dipiperidine (0.31 g; 1.25 mmol) wasdissolved in THF (10 mL) and added to the reaction mixture. Afterstirring for 16 h the reaction mixture was evaporated to dryness andpurified by prep. HPLC (method B). Yield: 200 mg. HPLC-MS: m/z: 566.1(M+); Rt: 2.13 min.

Step B:{4-[3-(4-Chloro-benzyloxy)-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid

{4-[3-(4-Chloro-benzyloxy)-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester (140 mg; 0.28 mmol) was dissolved in ethanol (15 mL),and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixturewas stirred for 1 h, acidified with 1 N aqueous hydrochloric acid, andextracted with ethyl acetate. The organic phase was dried and evaporatedto dryness. Yield: 180 mg. HPLC-MS: m/z: 538.0 (M+); Rt: 1.84 min.δ_(H)(400 MHz; CDCl₃) 2.27 (s, 3H), 3.15-3.30 (m, 2H), 3.45 (d, 2H),3.99-4.06 (m, 2H), 4.13-4.22 (m, 4H), 4.73 (s, 2H), 4.96 (s, 2H),6.57-6.60 (m, 1H), 6.74 (d, 1H), 6.76-6.81 (m, 2H), 7.25-7.31 (m, 4H),7.32-7.36 (m, 2H).

Example 11{2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-hydroxy-phenylsulfanyl]-phenoxy}-aceticacid

{2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-hydroxy-phenylsulfanyl]-phenoxy}-aceticacid ethyl ester (50 mg; 0.11 mmol) was dissolved in ethanol (6 mL), andaqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture wasstirred for 1 h, acidified with 1 N aqueous hydrochloric acid, andextracted with ethyl acetate. The organic phase was dried and evaporatedto dryness and purified by prep. HPLC (method B). Yield: 36 mg. HPLC-MS:m/z: 445.1 (M+); Rt: 2.44 min. Example 12{4-[3-But-2-ynyloxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid

Step A:{4-[3-But-2-ynyloxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester

4-[3-Hydroxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester (250 mg; 0.57 mmol), 2-butyn-1-ol (0.064 mL; 0.85 mmol)and tributyl-phosphine (0.31 mL; 1.25 mmol) were dissolved in THF (15mL) in a dried reaction flask under an atmosphere of nitrogen.1,1′-(Azodicarbonyl)dipiperidine (0.31 g; 1.25 mmol) was dissolved inTHF (10 mL) and added to the reaction mixture. After stirring for 16 hthe reaction mixture was evaporated to dryness and purified by prep.HPLC (method B). Yield: 150 mg. HPLC-MS: m/z: 494.0 (M+); Rt: 1.87 min.

Step B:{4-[3-But-2-ynyloxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid

{4-[3-But-2-ynyloxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester (150 mg; 0.30 mmol) was dissolved in ethanol (15 mL),and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixturewas stirred for 1 h, acidified with 1 N aqueous hydrochloric acid, andextracted with ethyl acetate. The organic phase was dried and evaporatedto dryness. Yield: 140 mg. HPLC-MS: m/z: 466.0 (M+); Rt: 1.60 min.

Example 13{2-Methyl-4-[3-(2-morpholin-4-yl-ethoxy)-5-phenylethynyl-phenylsulfanyl]-phenoxy}-aceticacid

Step A:{2-Methyl-4-[3-(2-morpholin-4-yl-ethoxy)-5-phenylethynyl-phenylsulfanyl]-phenoxy}-aceticacid ethyl ester

[4-(3-Hydroxy-5-phenylethynyl-phenylsulfanyl)-2-methyl-phenoxy]-aceticacid ethyl ester (200 mg; 0.48 mmol), 2-morpholin-4-yl-ethanol (0.22 g;0.67 mmol) and tributylphosphine (0.24 mL; 0.96 mmol) were dissolved inTHF (15 mL) in a dried reaction flask under an atmosphere of nitrogen.1,1′-(Azodicarbonyl)dipiperidine (0.24 g; 0.96 mmol) was dissolved inTHF (10 mL) and added to the reaction mixture. After stirring for 16 hthe reaction mixture was evaporated to dryness and purified by flashchromatography (ethyl acetate:heptane (1:3→1:9). Yield: 150 mg. HPLC-MS:m/z: 532.6 (M+H); Rt: 2.07 min.

Step B:{2-Methyl-4-[3-(2-morpholin-4-yl-ethoxy)-5-phenylethynyl-phenylsulfanyl]-phenoxy}-aceticacid

{2-Methyl-4-[3-(2-morpholin-4-yl-ethoxy)-5-phenylethynyl-phenylsulfanyl]-phenoxy}-aceticacid ethyl ester (150 mg; 0.30 mmol) was dissolved in ethanol (15 mL),and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixturewas stirred for 1 h, acidified with 1 N aqueous hydrochloric acid, andextracted with ethyl acetate. The organic phase was dried and evaporatedto dryness. Yield: 140 mg. HPLC-MS: m/z: 504.1 (M+); Rt: 1.80 min.

Example 14{2-Chloro-4-[3-(3-methoxy-prop-1-ynyl)-5-(3-morpholin-4-yl-propoxy)-phenyl-sulfanyl]-phenoxy}-aceticacid

Step A:{2-Chloro-4-[3-(3-methoxy-prop-1-ynyl)-5-(3-morpholin-4-yl-propoxy)-phenylsulfanyl]-phenoxy}-aceticacid ethyl ester

{4-[3-Bromo-5-(3-morpholin-4-yl-propoxy)-phenylsulfanyl]-2-chloro-phenoxy}-aceticacid ethyl ester (0.2 g; 0.37 mmol), 3-methoxy-propyne (0.10 g; 1.47mmol), bis(triphenylphosphine) palladium (II) chloride (21 mg; 0.029mmol) and copper iodide (4.2 mg; 0.022 mmol) were dissolved in a mixtureof triethylamine (2 mL) and DMF (2 mL) under an atmosphere of nitrogen.The reaction mixture was reacted in a microwave oven at 150° C. for 1 h.The reaction mixture was evaporated to dryness and extracted with ethylacetate from a aqueous 5% citric acid solution. The crude product wasdried, evaporated to dryness and purified by preparative HPLC (methodB). Yield: 160 mg. HPLC-MS: m/z: 534.1 (M+); Rt: 1.79 min.

Step B:{2-Chloro-4-[3-(3-methoxy-prop-1-ynyl)-5-(3-morpholin-4-yl-propoxy)-phenylsulfanyl]-phenoxy}-aceticacid

{2-Chloro-4-[3-(3-methoxy-prop-1-ynyl)-5-(3-morpholin-4-yl-propoxy)-phenyl-sulfanyl]-phenoxy}-aceticacid ethyl ester (150 mg; 0.30 mmol) was dissolved in ethanol (10 mL),and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixturewas stirred for 1 h, acidified with 1 N aqueous hydrochloric acid, andextracted with ethyl acetate. The organic phase was dried, andevaporated to dryness and purified by preparative HPLC (method B).Yield: 50 mg. HPLC-MS: m/z: 506.0 (M+); Rt: 1.56 min. δ_(H)(400 MHz;CDCl₃) 2.06-2.15 (m, 2H), 2.82-2.92 (m, 2H), 3.15-3.23 (m, 2H), 3.45 (s,3H), 3.56 (d, 2H), 3.78 (t, 2H), 3.95-4.03 (m, 4H), 4.30 (s, 2H), 4.89(s, 2H), 5.91-5.94 (m, 1H), 6.63-6.66 (m, 1H), 6.93 (d, 1H), 7.01-7.03(m, 1H), 7.40 (dd, 1H), 7.58 (d, 1H).

Example 15{2-Chloro-4-[3-(3-morpholin-4-yl-propoxy)-5-pent-1-ynyl-phenylsulfanyl]-phenoxy}-aceticacid

Step A:{2-Chloro-4-[3-(3-morpholin-4-yl-propoxy)-5-pent-1-ynyl-phenylsulfanyl]-phenoxy}-aceticacid ethyl ester

{4-[3-Bromo-5-(3-morpholin-4-yl-propoxy)-phenylsulfanyl]-2-chloro-phenoxy}-aceticacid ethyl ester (0.2 g; 0.37 mmol), 1-pentyne (0.10 g; 1.47 mmol),bis(triphenyl-phosphine)palladium (II) chloride (21 mg; 0.029 mmol) andcopper iodide (4.2 mg; 0.022 mmol) were dissolved in a mixture oftriethylamine (2 mL) and DMF (2 mL) under an atmosphere of nitrogen. Thereaction mixture was reacted in a microwave oven at 150° C. for 1 h. Thereaction mixture was evaporated to dryness and extracted with ethylacetate from a aqueous 5% citric acid solution. The crude product wasdried, evaporated to dryness and purified by preparative HPLC (methodB). Yield: 120 mg. HPLC-MS: m/z: 532.0 (M+); Rt: 2.02 min.

Step B:{2-Chloro-4-[3-(3-morpholin-4-yl-propoxy)-5-pent-1-ynyl-phenylsulfanyl]-phenoxy}-aceticacid

{2-Chloro-4-[3-(3-morpholin-4-yl-propoxy)-5-pent-1-ynyl-phenylsulfanyl]-phenoxy}-aceticacid ethyl ester (150 mg; 0.30 mmol) was dissolved in ethanol (10 mL),and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixturewas stirred for 1 h, acidified with 1 N aqueous hydrochloric acid, andextracted with ethyl acetate. The organic phase was dried, andevaporated to dryness and purified by preparative HPLC (method B).Yield: 70 mg. HPLC-MS: m/z: 504.1 (M+); Rt: 1.81 min.

Example 16{2-Methyl-4-[3-(3-morpholin-4-yl-propoxy)-5-(3-phenyl-prop-1-ynyl)-benzylsulfanyl]-phenoxy}-aceticacid

Step A:{2-Methyl-4-[3-(3-morpholin-4-yl-propoxy)-5-(3-phenyl-prop-1-ynyl)-benzylsulfanyl]-phenoxy}-aceticacid ethyl ester

{4-[3-Hydroxy-5-(3-phenyl-prop-1-ynyl)-benzylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester (200 mg; 0.45 mmol), 3-morpholin-4-yl-propan-1-ol (97.6mg; 0.67 mmol), tributylphosphine (0.27 mg; 1.34 mmol) and1,1′-(Azodicarbonyl)dipiperidine (0.34 g; 1.34 mmol) were dissolved inTHF (20 mL) in a dried reaction flask under an atmosphere of nitrogen.The reaction mixture was stirred for 1 h and purified by prep. HPLC(method A). Yield: 200 mg. HPLC-MS: m/z: 574.3 (M+H); Rt: 2.07 min.

Step B:{2-Methyl-4-[3-(3-morpholin-4-yl-propoxy)-5-(3-phenyl-prop-1-ynyl)-benzylsulfanyl]-phenoxy}-aceticacid

{2-Methyl-4-[3-(3-morpholin-4-yl-propoxy)-5-(3-phenyl-prop-1-ynyl)-benzylsulfanyl]-phenoxy}-aceticacid ethyl ester (150 mg; 0.30 mmol) was dissolved in ethanol (20 mL),and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixturewas stirred for 1 h, acidified with 1 N aqueous hydrochloric acid, andextracted with ethyl acetate. The organic phase was dried and evaporatedto dryness. Yield: 190 mg. HPLC-MS: m/z: 546.1 (M+); Rt: 1.85 min.

Example 17 {4-[3-(4-Fluoro-benzyloxy)-5-(3-morpholin-4-yl-prop-1ynyl)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid

Step A: {4-[3-(4-Fluoro-benzyloxy)-5-(3-morpholin-4-yl-prop-1ynyl)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester

{4-[3-Hydroxy-5-(3-morpholin-4-yl-prop-1-ynyl)-benzylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester (250 mg; 0.55 mmol), 1-fluoro-4-methoxymethyl-benzene(103.8 mg; 0.82 mmol), tributylphosphine (0.33 mg; 1.65 mmol) and1,1′-(azodicarbonyl)dipiperidine (0.414 g; 1.65 mmol) were dissolved inTHF (15 mL) in a dried reaction flask under an atmosphere of nitrogen.The reaction mixture was stirred for 16 h and purified by prep. HPLC(method A). Yield: 160 mg. HPLC-MS: m/z: 564.1 (M+H); Rt: 1.99 min.

Step B: {4-[3-(4-Fluoro-benzyloxy)-5-(3-morpholin-4-yl-prop-1ynyl)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid

{4-[3-(4-Fluoro-benzyloxy)-5-(3-morpholin-4-yl-prop-1ynyl)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (150 mg;0.30 mmol) was dissolved in ethanol (20 mL), and aqueous 1 N sodiumhydroxide (3 mL) was added. The reaction mixture was stirred for 1 h,acidified with 1 N aqueous hydrochloric acid, and extracted with ethylacetate. The organic phase was dried and evaporated to dryness. Yield:190 mg. HPLC-MS: m/z: 536.1 (M+); Rt: 1.76 min.

Example 18{2-Methyl-4-[3-(3-morpholin-4-yl-ethoxy)-5-(3-phenyl-prop-1-ynyl)-benzylsulfanyl]-phenoxy}-aceticacid

Step A:{2-Methyl-4-[3-(3-morpholin-4-yl-ethoxy)-5-(3-phenyl-prop-1-ynyl)-benzyl-sulfanyl]-phenoxy}-aceticacid ethyl ester

{4-[3-Hydroxy-5-(3-phenyl-prop-1-ynyl)-benzylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester (250 mg; 0.56 mmol), 3-morpholin-4-yl-propan-1-ol(110.1 mg; 0.84 mmol), tributylphosphine (0.34 mL; 1.68 mmol) and1,1′-(azodicarbonyl)dipiperidine (0.42 g; 1.68 mmol) were dissolved inTHF (15 mL) in a dried reaction flask under an atmosphere of nitrogen.After stirring for 2 h the reaction mixture was purified by prep. HPLC(method A). Yield: 50 mg. HPLC-MS: m/z: 560.2 (M+H); Rt: 2.03 min.

Step B:{2-Methyl-4-[3-(3-morpholin-4-yl-ethoxy)-5-(3-phenyl-prop-1-ynyl)-benzyl-sulfanyl]-phenoxy}-aceticacid

{2-Methyl-4-[3-(3-morpholin-4-yl-ethoxy)-5-(3-phenyl-prop-1-ynyl)-benzylsulfanyl]-phenoxy}-aceticacid ethyl ester (50 mg; 0.09 mmol) was dissolved in ethanol (10 mL),and aqueous 1 N sodium hydroxide (2 mL) was added. The reaction mixturewas stirred for 16 h, acidified with 1 N aqueous hydrochloric acid andextracted with dichloromethane. The organic phase was dried andevaporated to dryness. Yield: 45 mg. HPLC-MS: m/z: 532.1 (M+); Rt: 1.79min.

Example 19{4-[3-Cyclohexylmethoxy-5-(4-methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid

Step A:{4-[3-Cyclohexylmethoxy-5-(4-methanesulfonyl-phenylethynyl)-phenyl-sulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester

[4-(3-Bromo-5-cyclohexylmethoxy-phenylsulfanyl)-2-methyl-phenoxy]-aceticacid ethyl acetate (0.1 g; 0.203 mmol),1-Ethynyl-4-methanesulfonyl-benzene (0.109 g; 0.61 mmol),bis(triphenylphosphine)palladium (II) chloride (11.4 mg; 0.016 mmol) andcopper iodide (2.3 mg; 0.06 mmol) were dissolved in a mixture oftriethylamine (2 mL) and DMF (2 mL) under an atmosphere of nitrogen. Thereaction mixture was reacted in a microwave oven at 120° C. for 1 h.Water and dichloromethane was added to the reaction mixture and thephases were separated and washed with water. The organic phase was driedand evaporated to dryness. The crude product was purified by prep. HPLC(Metode A). Yield: 90 mg. HPLC-MS: m/z: 593.5 (M+H)+; Rt: 3.04 min.

Step B:{4-[3-Cyclohexylmethoxy-5-(4-methanesulfonyl-phenylethynyl)-phenyl-sulfanyl]-2-methyl-phenoxy}-aceticacid

{4-[3-Cyclohexylmethoxy-5-(4-methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester (120 mg; 0.202 mmol) was dissolved in ethanol (50 mL),and aqueous 1 N sodium hydroxide (2 mL) was added. The reaction mixturewas stirred for 30 min, acidified with 1 N aqueous hydrochloric acid andextracted with dichloromethane. The organic phase was dried andevaporated to dryness. Yield: 90 mg. HPLC-MS: m/z: 565.3 (M+H)+; Rt:2.81 min.

Example 20{4-[3-Cyclopentylmethoxy-5-(4-methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid

Step A:{4-[3-Cyclopentylmethoxy-5-(4-methanesulfonyl-phenylethynyl)-phenyl-sulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester

[4-(3-Bromo-5-cyclopentylmethoxy-phenylsulfanyl)-2-methyl-phenoxy]-aceticacid ethyl acetate (0.24 g; 0.50 mmol),1-Ethynyl-4-methanesulfonyl-benzene (0.271 g; 1.5 mmol),bis(triphenylphosphine)palladium (II) chloride (28.11 mg; 0.04 mmol) andcopper iodide (5.7 mg; 0.03 mmol) were dissolved in a mixture oftriethylamine (5 mL) and DMF (5 mL) under an atmosphere of nitrogen. Thereaction mixture was reacted in a microwave oven at 120° C. for 1 h.Water and dichloromethane was added to the reaction mixture and thephases were separated and washed with water. The organic phase was driedand evaporated to dryness. The crude product was purified by prep. HPLC(Metode A). Yield: 180 mg. HPLC-MS: m/z: 579.4 (M+H)+; Rt: 3.00 min.

Step B:{4-[3-Cyclopentylmethoxy-5-(4-methanesulfonyl-phenylethynyl)-phenyl-sulfanyl]-2-methyl-phenoxy}-aceticacid

{4-[3-Cyclopentylmethoxy-5-(4-methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester (120 mg; 0.202 mmol) was dissolved in ethanol (50 mL),and aqueous 1 N sodium hydroxide (2 mL) was added. The reaction mixturewas stirred for 30 min, acidified with 1 N aqueous hydrochloric acid andextracted with dichloromethane. The organic phase was dried andevaporated to dryness. Yield: 100 mg. HPLC-MS: m/z: 551.5 (M+H)+; Rt:2.69 min.

Example 21{4-[3-Isobutoxy-5-(4-methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid

Step A:{4-[3-Isobutoxy-5-(4-methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester

The title product was prepared as described for{4-[3-Cyclopentylmethoxy-5-(4-methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester. The crude product was purified by prep. HPLC (methodB). Yield: 52%. HPLC-MS: m/z: 552.7 (M)+; Rt: 2.88 min.

Step B:{4-[3-Isobutoxy-5-(4-methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid

{4-[3-Isobutoxy-5-(4-methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester (190 mg; 0.34 mmol) was dissolved in ethanol (10 mL),and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixturewas stirred for 16 h. acidified with 1 N aqueous hydrochloric acid andextracted with ethyl acetate. The organic phase was dried and evaporatedto dryness and purified by prep HPLC (method B). Yield: 110 mg (61%).HPLC-MS: m/z: 525.1 (M+H)+; Rt: 2.55 min.

Example 22{4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid

Step A:{4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester

The title product was prepared as described for{4-[3-Cyclopentylmethoxy-5-(4-methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester. The crude product was purified by prep. HPLC (methodB). Yield: 64%. HPLC-MS: m/z: 635.4 (M+H)+; Rt: 2.92 min.

Step B:{4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid

{4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-methanesulfonyl-phenylethynyl)-phenyl-sulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester (190 mg; 0.30 mmol) was dissolved in ethanol (15 mL),and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixturewas stirred for 16 h. acidified with 1 N aqueous hydrochloric acid andextracted with ethyl acetate. The organic phase was dried and evaporatedto dryness and purified by prep HPLC (method B). Yield: 160 mg (89%).HPLC-MS: m/z: 607.1 (M+H)+; Rt: 2.82 min.

Example 23{4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid

Step A:{4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester

(4-{3-Bromo-5-[2-(4-chloro-phenyl)-ethoxy]-phenylsulfanyl}-2-methyl-phenoxy)-aceticacid ethyl ester (300 mg; 0.56 mmol), 4-prop-2-ynyl-morpholine (280.4mg; 2.2 mmol), bis(triphenylphosphine) palladium (II) chloride (31.4 mg;0.045 mmol) and copper iodide (6.4 mg; 0.034 mmol) were dissolved in amixture of triethylamine (2 mL) and DMF (2 mL) under an atmosphere ofnitrogen. The reaction mixture was reacted in a microwave oven at 110°C. for 1.5 h. The reaction mixture was evaporated to dryness, and 5%aqueous citric acid (30 mL) and ethyl acetate (30 mL) was added. The twophases were separated and the aqueous phase was extracted with ethylacetate (30 mL). The combined organic phases were dried and evaporatedto dryness and purified by preparative HPLC (method B). Yield: 300 mg;92%. HPLC-MS: m/z: 580.7 (M+H)+; Rt: 2.16 min.

Step B:{4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(3-morpholin-4-yl-prop-1-ynyl)-phenyl-sulfanyl]-2-methyl-phenoxy}-aceticacid

{4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester (190 mg; 0.30 mmol) was dissolved in ethanol (25 mL),and aqueous 1 N sodium hydroxide (5 mL) was added. The reaction mixturewas stirred for 16 h. acidified with 1 N aqueous hydrochloric acid andextracted with ethyl acetate. The organic phase was dried and evaporatedto dryness, redissolved in dichloromethane and evaporated to dryness.Yield: 250 mg (87%). HPLC-MS: m/z: 552.8 (M+H)+; Rt: 1.90 min.

Example 24{4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenyl-sulfanyl]-2-methyl-phenoxy}-aceticacid

Step A:{4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester

(4-{3-Bromo-5-[2-(4-chloro-phenyl)-ethoxy]-phenylsulfanyl}-2-methyl-phenoxy)-aceticacid ethyl ester (270 mg; 0.46 mmol), (4-ethynyl-phenyl)-methanol (296mg; 2.2 mmol), bis(triphenylphosphine) palladium (II) chloride (31.4 mg;0.045 mmol) and copper iodide (6.4 mg; 0.034 mmol) were dissolved in amixture of triethylamine (2 mL) and DMF (2 mL) under an atmosphere ofnitrogen. The reaction mixture was reacted in a microwave oven at 110°C. for 1.5 h. The reaction mixture was evaporated to dryness, and 5%aqueous citric acid (30 mL) and ethyl acetate (30 mL) was added. The twophases were separated and the aqueous phase was extracted with ethylacetate (30 mL). The combined organic phases were dried and evaporatedto dryness and purified by preparative HPLC (method B). Yield: 270 mg(83%). HPLC-MS: m/z: 587.1 (M+H)+; Rt: 2.96 min.

Step B:{4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid

{4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenyl-sulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester (270 mg; 0.46 mmol) was dissolved in ethanol (15 mL),and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixturewas stirred for 16 h. acidified with 1 N aqueous hydrochloric acid andextracted with ethyl acetate. The organic phase was dried, evaporated todryness and purified by prep HPLC (method B). Yield: 218 mg (85%).HPLC-MS: m/z: 559.1 (M+H)+; Rt: 2.61 min.

Example 25{4-[3-(2-Ethyl-butoxy)-5-phenylethynyl-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid

Step A:{4-[3-(2-Ethyl-butoxy)-5-phenylethynyl-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester

The title product was prepared from{4-[3-Bromo-5-(2-ethyl-butoxy)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester (200 mg; 0.42 mmol), (phenyl acetylene (170 mg; 1.66mmol) applying the procedure described for{4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester. The crude product was purified by preparative HPLC(method B). Yield: 170 mg (82%). HPLC-MS: m/z: 502.9 (M)+; Rt: 3.32 min.

Step B:{4-[3-(2-Ethyl-butoxy)-5-phenylethynyl-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid

{4-[3-(2-Ethyl-butoxy)-5-phenylethynyl-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester (270 mg; 0.46 mmol) was dissolved in ethanol (10 mL),and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixturewas stirred for 16 h. acidified with 1 N aqueous hydrochloric acid andextracted with ethyl acetate. The organic phase was dried, evaporated todryness and purified by prep HPLC (method B). Yield: 128 mg (80%).HPLC-MS: m/z: 475.1 (M+H)+; Rt: 3.06 min.

Example 26[4-(3-Cyclopentyloxy-5-phenylethynyl-phenylsulfanyl)-2-methyl-phenoxy]-aceticacid

Step A:[4-(3-Cyclopentyloxy-5-phenylethynyl-phenylsulfanyl)-2-methyl-phenoxy]-aceticacid ethyl ester

The title product was prepared from[4-(3-Bromo-5-cyclopentyloxy-phenylsulfanyl)-2-methyl-phenoxy]-aceticacid ethyl ester (250 mg; 0.54 mmol), (phenyl acetylene (110 mg; 1.07mmol) applying the procedure described for{4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester. The crude product was purified by preparative HPLC(method B). Yield: 186 mg (70%). HPLC-MS: m/z: 487.1 (M+H)+; Rt: 3.17min.

Step B:[4-(3-Cyclopentyloxy-5-phenylethynyl-phenylsulfanyl)-2-methyl-phenoxy]-aceticacid

{[4-(3-Cyclopentyloxy-5-phenylethynyl-phenylsulfanyl)-2-methyl-phenoxy]-aceticacid ethyl ester (270 mg; 0.46 mmol) was dissolved in ethanol (10 mL),and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixturewas stirred for 16 h. acidified with 1 N aqueous hydrochloric acid andextracted with ethyl acetate. The organic phase was dried, evaporated todryness and purified by prep HPLC (method B). Yield: 120 mg (69%).HPLC-MS: m/z: 459.1 (M+H)+; Rt: 2.86 min.

Example 27{4-[3-(4-Fluoro-phenylethynyl)-5-(4-methanesulfonyl-benzyloxy)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid

Step A:{4-[3-(4-Fluoro-phenylethynyl)-5-(4-methanesulfonyl-benzyloxy)-phenyl-sulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester

The title product was prepared from{4-[3-Bromo-5-(4-methanesulfonyl-benzyloxy)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester (335 mg; 0.59 mmol), 1-ethynyl-4-fluorobenzene (142.3mg; 1.19 mmol) applying the procedure described for{4-[3-[2-(4-Chlorophenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester. The crude product was purified by preparative HPLC(method B). Yield: 140 mg (39%). HPLC-MS: m/z: 605.5 (M+H)+; Rt: 2.80min.

Step B:{4-[3-(4-Fluoro-phenylethynyl)-5-(4-methanesulfonyl-benzyloxy)-phenyl-sulfanyl]-2-methyl-phenoxy}-aceticacid

{4-[3-(4-Fluoro-phenylethynyl)-5-(4-methanesulfonyl-benzyloxy)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester (270 mg; 0.46 mmol) was dissolved in ethanol (15 mL),and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixturewas stirred for 16 h. acidified with 1 N aqueous hydrochloric acid andextracted with ethyl acetate. The organic phase was dried, evaporated todryness and purified by prep HPLC (method B). Yield: 113 mg (85%).HPLC-MS: m/z: 599.4 (M+Na); Rt: 2.50 min.

Example 28[4-(3-Cyclopentylmethoxy-5-phenylethynyl-phenylsulfanyl)-2-methyl-phenoxy]-aceticacid

Step A:[4-(3-Cyclopentylmethoxy-5-phenylethynyl-phenylsulfanyl)-2-methyl-phenoxy]-aceticacid ethyl ester

The title product was prepared from[4-(3-Bromo-5-cyclopentyloxy-phenylsulfanyl)-2-methyl-phenoxy]-aceticacid ethyl ester (300 mg; 0.63 mmol), phenylacetylen (191.7 mg; 1.88mmol) applying the procedure described for{4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester. The crude product was purified by preparative HPLC(method B). Yield: 200 mg (64%). HPLC-MS: m/z: 500.8 (M)+; Rt: 3.30 min.

Step B:[4-(3-Cyclopentylmethoxy-5-phenylethynyl-phenylsulfanyl)-2-methyl-phenoxy]-aceticacid

{[4-(3-Cyclopentylmethoxy-5-phenylethynyl-phenylsulfanyl)-2-methyl-phenoxy]-aceticacid ethyl ester (200 mg; 0.40 mmol) was dissolved in THF (2 mL),ethanol (4 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. Thereaction mixture was stirred for 30 min. acidified with 1 N aqueoushydrochloric acid and extracted with ethyl acetate. The organic phasewas dried and evaporated to dryness. Yield: 146 mg (78%). HPLC-MS: m/z:472.9 (M)+; Rt: 3.03 min.

Example 29{4-[3-(2-Cyclohexyl-ethoxy)-5-phenylethynyl-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid

Step A:{4-[3-(2-Cyclohexyl-ethoxy)-5-phenylethynyl-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester

The title product was prepared from{4-[3-Bromo-5-(2-cyclohexyl-ethoxy)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester (300 mg; 0.58 mmol), phenylacetylen (181.1 mg; 1.8mmol) applying the procedure described for{4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester. The crude product was purified by preparative HPLC(method B). Yield: 110 mg (33%). HPLC-MS: m/z: 529.6 (M+H)+; Rt: 3.38min.

Step B:{4-[3-(2-Cyclohexyl-ethoxy)-5-phenylethynyl-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid

{4-[3-(2-Cyclohexyl-ethoxy)-5-phenylethynyl-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester (110 mg; 0.208 mmol) was dissolved in THF (2 mL),ethanol (4 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. Thereaction mixture was stirred for 30 min. acidified with 1 N aqueoushydrochloric acid and extracted with ethyl acetate. The organic phasewas dried and evaporated to dryness. Yield: 105 mg. HPLC-MS: m/z: 500.1(M)+; Rt: 3.20 min.

Example 30{4-[3-(2-Ethyl-butoxy)-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid

Step A:{4-[3-(2-Ethyl-butoxy)-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester

The title product was prepared from4-(3-Bromo-5-cyclopentyloxy-phenylsulfanyl)-2-methyl-phenoxy]-aceticacid ethyl ester (200 mg; 0.42 mmol) and 4-prop-2-ynyl-morpholine (156.0mg; 1.26 mmol) applying the procedure described for{4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester. The crude product was purified by preparative HPLC(method B). Yield: 210 mg (95%). HPLC-MS: m/z: 526.2 (M+H)+; Rt: 2.23min

Step B:{4-[3-(2-Ethyl-butoxy)-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid

{4-[3-(2-Ethyl-butoxy)-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester (210 mg; 0.40 mmol) was dissolved in ethanol (10 mL),and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixturewas stirred for 16 h. acidified with 1 N aqueous hydrochloric acid andextracted with ethyl acetate. The organic phase was dried and evaporatedto dryness and purified by prep HPLC (method B). Yield: 144 mg (73%).HPLC-MS: m/z: 498.2 (M+H)+; Rt: 1.97 min.

Example 31{4-[3-Cyclopentyloxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid

Step A:{4-[3-Cyclopentyloxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester

The title product was prepared from[4-(3-Bromo-5-cyclopentyloxy-phenylsulfanyl)-2-methyl-phenoxy]-aceticacid ethyl ester (250 mg; 0.54 mmol) and 4-prop-2-ynyl-morpholine(134.48 mg; 1.07 mmol) applying the procedure described for{4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester. The crude product was purified by preparative HPLC(method B). Yield: 210 mg (95%). HPLC-MS: m/z: 510.2 (M+H)+; Rt: 2.03min

Step B:{4-[3-Cyclopentyloxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid

{4-[3-Cyclopentyloxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester (160 mg; 0.31 mmol) was dissolved in ethanol (10 mL),and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixturewas stirred for 16 h. acidified with 1 N aqueous hydrochloric acid andextracted with ethyl acetate. The organic phase was dried and evaporatedto dryness and purified by prep HPLC (method B). Yield: 105 mg (70%).HPLC-MS: m/z: 482.2 (M+H)+; Rt: 1.77 min.

Example 32{4-[3-(2-Cyclohexyl-ethoxy)-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid

Step A:{4-[3-(2-Cyclohexyl-ethoxy)-5-(3-morpholin-4-yl-prop-1-ynyl)-phenyl-sulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester

The title product was prepared from{4-[3-Bromo-5-(2-cyclohexyl-ethoxy)-phenyl-sulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester (300 mg; 0.59 mmol) and 4-prop-2-ynyl-morpholine (222.0mg; 1.77 mmol) applying the procedure described for{4-[3-[2-(4-Chlorophenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester. The crude product was purified by preparative HPLC(method B). Yield: 200 mg (30%). HPLC-MS: m/z: 551.8 (M)+; Rt: 2.35 min

Step B:{4-[3-(2-Cyclohexyl-ethoxy)-5-(3-morpholin-4-yl-prop-1-ynyl)-phenyl-sulfanyl]-2-methyl-phenoxy}-aceticacid

{4-[3-(2-Cyclohexyl-ethoxy)-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester (200 mg; 0.36 mmol) was dissolved in THF (2 mL) andethanol (4 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. Thereaction mixture was stirred for 30 min. acidified with 1 N aqueoushydrochloric acid and extracted with ethyl acetate. The organic phasewas dried and evaporated to dryness. Yield: 107 mg (57%). HPLC-MS: m/z:523.9 (M)+; Rt: 2.06 min.

Example 33{4-[3-Cyclopentylmethoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid

Step A:{4-[3-(2-Cyclohexyl-ethoxy)-5-(3-morpholin-4-yl-prop-1-ynyl)-phenyl-sulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester

The title product was prepared from{4-[3-Bromo-5-cyclopentylmethoxy-phenyl-sulfanyl)-2-methyl-phenoxy]-aceticacid ethyl ester (260 mg; 0.54 mmol) and 4-prop-2-ynyl-morpholine (203.6mg; 1.63 mmol) applying the procedure described for{4-[3-[2-(4-Chlorophenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester. The crude product was purified by preparative HPLC(method B). Yield: 80 mg (28%). HPLC-MS: m/z: 523.9 (M)+; Rt: 2.19 min

Step B:{4-[3-Cyclopentylmethoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid

{4-[3-Cyclopentylmethoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester (80 mg; 0.15 mmol) was dissolved in THF (2 mL) andethanol (4 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. Thereaction mixture was stirred for 30 min. acidified with 1 N aqueoushydrochloric acid and extracted with ethyl acetate. The organic phasewas dried and evaporated to dryness. Yield: 43 mg (57%). HPLC-MS: m/z:495.8 (M)+; Rt: 1.92 min.

Example 34{4-[3-Cyclopentylmethoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic

Step A:{4-[3-Cyclopentylmethoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticethyl ester

The title product was prepared from{4-[3-Hydroxy-5-(3-morpholin-4-yl-prop-1-ynyl)-benzylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester (350 mg; 0.77 mmol), cyclohexylmethanol (131.6 mg; 1.15mmol), tributylphosphine (0.465 mg; 2.31 mmol) and1,1′-(azodicarbonyl)dipiperidine (0.581 g; 2.31 mmol) were dissolved inTHF (50 mL) in a dried reaction flask under an atmosphere of nitrogen.The reaction mixture was stirred for 16 h and purified by columnchromatography; ethyl acetate:heptane (5:1). Yield: 120 mg. HPLC-MS:m/z: 552.1 (M+H)+; Rt: 2.19 min.

Step B:{4-[3-Cyclopentylmethoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic

{4-[3-Cyclopentylmethoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticethyl ester (120 mg; 0.22 mmol) was dissolved in THF (2 mL) and ethanol(8 mL), and aqueous 1 N sodium hydroxide (2 mL) was added. The reactionmixture was stirred for 16 h. acidified with 1 N aqueous hydrochloricacid and extracted with ethyl acetate. The organic phase was dried andevaporated to dryness. Yield: 110 mg (90%). HPLC-MS: m/z: 524.2 (M+H)+;Rt: 1.97 min.

Example 35{4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-benzylsulfanyl]-2-methyl-phenoxy}-aceticacid

Step A:{4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-benzylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester

The title product was prepared from[4-(3-Bromo-5-isobutoxy-benzylsulfanyl)-2-methyl-phenoxy]-acetic acidethyl ester (300 mg; 0.64 mmol) and 4-prop-2-ynyl-morpholine (221 mg;2.6 mmol) applying the procedure described for{4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester. The crude product was purified by preparative HPLC(method B). Yield: 140 mg (44%). HPLC-MS: m/z: 511.9 (M)+; Rt: 2.00 min.

Step B:{4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-benzylsulfanyl]-2-methyl-phenoxy}-aceticacid

{{4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-benzylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester (140 mg; 0.27 mmol) was dissolved in ethanol (15 mL),and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixturewas stirred for 16 h. acidified with 1 N aqueous hydrochloric acid andextracted with ethyl acetate. The organic phase was dried and evaporatedto dryness, redissolved in dichloromethane and evaporated to dryness.Yield: 113 mg (86%). HPLC-MS: m/z: 484.9 (M+H)+; Rt: 1.70 min. δ_(H)(400MHz; CDCl₃) 1.03 (d, 6H), 2.04-2.12 (m, 1H), 2.24 (s, 3H), 2.90-3.30 (m,2H), 3.40-3.70 (m, 2H), 3.71 (d, 2H), 3.74 (s, 2H), 3.95-4.05 (m, 4H),4.17 (s, 2H), 4.69 (s, 2H), 6.14 (m, 1H), 6.53 (d, 1H), 6.77 (dd, 1H),6.81 (m, 1H), 6.89 (m, 1H), 7.23 (d, 1H).

Example 36[4-(3-Isobutoxy-5-phenylethynyl-benzylsulfanyl)-2-methyl-phenoxy]-aceticacid

Step A:[4-(3-Isobutoxy-5-phenylethynyl-benzylsulfanyl)-2-methyl-phenoxy]-aceticacid ethyl ester

The title product was prepared from[4-(3-Bromo-5-isobutoxy-benzylsulfanyl)-2-methyl-phenoxy]-acetic acidethyl ester (300 mg; 0.64 mmol) and phenylacetylen (262 mg; 2.6 mmol)applying the procedure described for{4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester. The crude product was purified by preparative HPLC(method B). Yield: 130 mg (45%). HPLC-MS: m/z: 489.1 (M+H)+; Rt: 3.01min

Step B:[4-(3-Isobutoxy-5-phenylethynyl-benzylsulfanyl)-2-methyl-phenoxy]-aceticacid

[4-(3-Isobutoxy-5-phenylethynyl-benzylsulfanyl)-2-methyl-phenoxy]-aceticacid ethyl ester (130 mg; 0.27 mmol) was dissolved in ethanol (15 mL),and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixturewas stirred for 16 h. acidified with 1 N aqueous hydrochloric acid andextracted with ethyl acetate. The organic phase was dried and evaporatedto dryness, redissolved in dichloromethane and evaporated to dryness.Yield: 120 mg (97%). HPLC-MS: m/z: 461.7 (M+H)+; Rt: 2.82 min.

Example 37{4-[3-Isobutoxy-5-(4-methanesulfonyl-phenylethynyl)-benzylsulfanyl]-2-methyl-phenoxy}-aceticacid

Step A:[{4-[3-Isobutoxy-5-(4-methanesulfonyl-phenylethynyl)-benzylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester

The title product was prepared from[4-(3-Bromo-5-isobutoxy-benzylsulfanyl)-2-methyl-phenoxy]-acetic acidethyl ester (300 mg; 0.64 mmol) and 1-Ethynyl-4-methanesulfonyl-benzene(347.0 mg; 1.93 mmol) applying the procedure described for{4-[3-[2-(4-Chlorophenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester. The crude product was purified by preparative HPLC(method A). Yield: 260 mg (72%). HPLC-MS: m/z: 567.6 (M+H)+; Rt: 2.77min

Step B:{4-[3-Isobutoxy-5-(4-methanesulfonyl-phenylethynyl)-benzylsulfanyl]-2-methyl-phenoxy}-aceticacid

{4-[3-Isobutoxy-5-(4-methanesulfonyl-phenylethynyl)-benzylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester (130 mg; 0.27 mmol) was dissolved in ethanol (15 mL),and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixturewas stirred for 16 h. acidified with 1 N aqueous hydrochloric acid andextracted with ethyl acetate. The organic phase was dried and evaporatedto dryness, redissolved in dichloromethane and evaporated to dryness.Yield: 230 mg (%). HPLC-MS: m/z: 539.5 (M+H)+; Rt: 2.49 min.

Example 38{4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(5-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid

Step A:{4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(5-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester

The title product was prepared from{4-[3-Bromo-5-(5-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester (250 mg; 0.46 mmol) and1-Ethynyl-4-methanesulfonyl-benzene (249.2 mg; 1.38 mmol) applying theprocedure described for{4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester. The crude product was purified by preparative HPLC(method B). Yield: 168 mg (57%). HPLC-MS: m/z: 642.1 (M+H)+; Rt: 2.75min

Step B:{4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(5-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid

{{4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(5-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester (168 mg; 0.26 mmol) was dissolved in ethanol (15 mL),and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixturewas stirred for 16 h. acidified with 1 N aqueous hydrochloric acid andextracted with ethyl acetate, dried and evaporated to dryness. Theorganic phase was purified by preparative HPLC (method B). Yield: 120 mg(75%). HPLC-MS: m/z: 614.1 (M+H)+; Rt: 2.45 min.

Example 39{4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(3-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid

Step A:{4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(3-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester

The title product was prepared from{4-[3-Bromo-5-(3-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester (250 mg; 0.46 mmol) and1-Ethynyl-4-methanesulfonyl-benzene (249.2 mg; 1.38 mmol) applying theprocedure described for{4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester. The crude product was purified by preparative HPLC(method B). Yield: 197 mg (67%). HPLC-MS: m/z: 642.4 (M+H)+; Rt: 2.73min

Step B:{4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(3-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid

{4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(3-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester (197 mg; 0.31 mmol) was dissolved in ethanol (15 mL),and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixturewas stirred for 16 h. acidified with 1 N aqueous hydrochloric acid andextracted with ethyl acetate, dried and evaporated to dryness. Theorganic phase was purified by preparative HPLC (method B). Yield: 150 mg(80%). HPLC-MS: m/z: 614.4 (M+H)+; Rt: 2.42 min.

Example 40{2-Methyl-4-[3-(3-morpholin-4-yl-prop-1-ynyl)-5-(3-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-phenoxy}-aceticacid

Step A:{2-Methyl-4-[3-(3-morpholin-4-yl-prop-1-ynyl)-5-(3-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-phenoxy}-aceticacid ethyl ester

The title product was prepared from{4-[3-Bromo-5-(3-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester (250 mg; 0.46 mmol) and 4-prop-2-ynyl-morpholine(173.09 mg; 1.38 mmol) applying the procedure described for{4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methylphenoxy}-aceticacid ethyl ester. The crude product was purified by preparative HPLC(method B). Yield: 262 mg (97%). HPLC-MS: m/z: 587.5 (M+H)+; Rt: 2.03min

Step B:{2-Methyl-4-[3-(3-morpholin-4-yl-prop-1-ynyl)-5-(3-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-phenoxy}-aceticacid

{2-Methyl-4-[3-(3-morpholin-4-yl-prop-1-ynyl)-5-(3-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-phenoxy}-aceticacid ethyl ester (262 mg; 0.45 mmol) was dissolved in ethanol (15 mL),and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixturewas stirred for 16 h. acidified with 1 N aqueous hydrochloric acid andextracted with ethyl acetate, dried and evaporated to dryness. Theorganic phase was purified by preparative HPLC (method B). Yield: 178 mg(72%). HPLC-MS: m/z: 559.5 (M+H)+; Rt: 1.78 min.

Example 41{2-Methyl-4-[3-(3-morpholin-4-yl-prop-1-ynyl)-5-(5-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-phenoxy}-aceticacid

Step A:{2-Methyl-4-[3-(3-morpholin-4-yl-prop-1-ynyl)-5-(5-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-phenoxy}-aceticacid ethyl ester

The title product was prepared from{4-[3-Bromo-5-(5-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester (250 mg; 0.46 mmol) and 4-prop-2-ynyl-morpholine(173.09 mg; 1.38 mmol) applying the procedure described for{4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester. The crude product was purified by preparative HPLC(method B). Yield: 270 mg (100%). HPLC-MS: m/z: 587.5 (M+H)+; Rt: 2.03min

Step B:{2-Methyl-4-[3-(3-morpholin-4-yl-prop-1-ynyl)-5-(5-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-phenoxy}-aceticacid

{2-Methyl-4-[3-(3-morpholin-4-yl-prop-1-ynyl)-5-(5-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-phenoxy}-aceticacid ethyl ester (262 mg; 0.45 mmol) was dissolved in ethanol (15 mL),and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixturewas stirred for 16 h. acidified with 1 N aqueous hydrochloric acid andextracted with ethyl acetate, dried and evaporated to dryness. Theorganic phase was purified by preparative HPLC (method B). Yield: 174 mg(68%). HPLC-MS: m/z: 559.5 (M+H)+; Rt: 1.81 min.

Example 42{2-Methyl-4-[3-(3-morpholin-4-yl-prop-1-ynyl)-5-(3-trifluoromethyl-phenoxy)-phenylsulfanyl]-phenoxy}-aceticacid

Step A:{2-Methyl-4-[3-(3-morpholin-4-yl-prop-1-ynyl)-5-(3-trifluoromethyl-phenoxy)-phenylsulfanyl]-phenoxy}-aceticacid ethyl ester

The title product was prepared from{4-[3-Bromo-5-(3-trifluoromethyl-phenoxy)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester (230 mg; 0.43 mmol) and 4-prop-2-ynyl-morpholine (159.5mg; 1.28 mmol) applying the procedure described for{4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester. The crude product was purified by preparative HPLC(method A). Yield: 160 mg. HPLC-MS: m/z: 586.5 (M+H)+; Rt: 2.18 min

Step B:{2-Methyl-4-[3-(3-morpholin-4-yl-prop-1-ynyl)-5-(3-trifluoromethyl-phenoxy)-phenylsulfanyl]-phenoxy}-aceticacid

{2-Methyl-4-[3-(3-morpholin-4-yl-prop-1-ynyl)-5-(3-trifluoromethyl-phenoxy)-phenylsulfanyl]-phenoxy}-aceticacid ethyl ester (160 mg; 0.27 mmol) was dissolved in ethanol (15 mL),and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixturewas stirred for 16 h. acidified with 1 N aqueous hydrochloric acid andextracted with ethyl acetate, dried and evaporated to dryness. Theorganic phase was purified by preparative HPLC (method B). Yield: 128 mg(84%). HPLC-MS: m/z: 558.4 (M+H)+; Rt: 1.91 min. δ_(H)(400 MHz; CDCl₃)2.26 (s, 3H), 3.05-3.55 (m, 4H), 3.91-4.04 (m, 4H), 4.11 (s, 2H), 4.70(s, 2H), 6.71-6.78 (m, 3H), 6.81-6.84 (m, 1H), 7.11-7.16 (m, 1H),7.19-7.23 (m, 1H), 7.27-7.33 (m, 2H), 7.37-7.41 (m, 1H), 7.43-7.49 (m,1H).

Example 43{4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(3-trifluoromethyl-phenoxy)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid

Step A:{4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(3-trifluoromethyl-phenoxy)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester

The title product was prepared from{4-[3-Bromo-5-(3-trifluoromethyl-phenoxy)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester (230 mg; 0.43 mmol) and1-Ethynyl-4-methanesulfonyl-benzene (229.7 mg; 1.28 mmol) applying theprocedure described for{4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester. The crude product was purified by preparative HPLC(method A). Yield: 140 mg. HPLC-MS: m/z: 641.5 (M+H)+; Rt: 2.89 min

Step B:{4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(3-trifluoromethyl-phenoxy)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid

{4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(3-trifluoromethyl-phenoxy)-phenyl-sulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester (140 mg; 0.22 mmol) was dissolved in ethanol (15 mL),and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixturewas stirred for 16 h. acidified with 1 N aqueous hydrochloric acid andextracted with ethyl acetate, dried and evaporated to dryness. Theorganic phase was purified by preparative HPLC (method B). Yield: 100 mg(75%). HPLC-MS: m/z: 635.1 (M+Na); Rt: 2.62 min.

Example 44{2-Methyl-4-[3-phenylethynyl-5-(5-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-phenoxy}-aceticacid

Step A:{2-Methyl-4-[3-phenylethynyl-5-(5-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-phenoxy}-aceticacid ethyl ester

The title product was prepared from{4-[3-Bromo-5-(3-trifluoromethyl-phenoxy)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester (300 mg; 0.55 mmol) and phenylacetylene (113 mg; 1.11mmol) applying the procedure described for{4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester. The crude product was purified by preparative HPLC(method A). Yield: 150 mg. HPLC-MS: m/z: 564.5 (M+H)+; Rt: 3.00 min

Step B:{2-Methyl-4-[3-phenylethynyl-5-(5-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-phenoxy}-aceticacid

{2-Methyl-4-[3-phenylethynyl-5-(5-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-phenoxy}-aceticacid ethyl ester (150 mg; 0.266 mmol) was dissolved in THF (2 mL) andethanol (4 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. Thereaction mixture was stirred for ½ h. acidified with 5% aqueous citricacid and extracted with ethyl acetate, dried and evaporated to dryness.Yield: 100 mg (75%). HPLC-MS: m/z: 535.7 (M)+; Rt: 2.78 min.

Example 45{4-[3-Cyclopropylmethoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-benzylsulfanyl]-2-methyl-phenoxy}-aceticacid

Step A:{4-[3-Cyclopropylmethoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-benzylsulfanyl]-2-methyl-phenoxy}-aceticacid acid ethyl ester

The title product was prepared from[4-(3-Bromo-5-cyclopropylmethoxy-benzylsulfanyl)-2-methyl-phenoxy]-aceticacid ethyl ester (200 mg; 0.43 mmol) and 4-prop-2-ynyl-morpholine (161mg; 1.3 mmol) applying the procedure described for{4-[3-[2-(4-Chlorophenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester. The crude product was purified by preparative HPLC(method B). Yield: 173 mg; 79%. HPLC-MS: m/z: 510.1 (M)+; Rt: 1.9 min.

Step B:{4-[3-Cyclopropylmethoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-benzylsulfanyl]-2-methyl-phenoxy}-aceticacid

{4-[3-Cyclopropylmethoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-benzylsulfanyl]-2-methyl-phenoxy}-aceticacid acid ethyl ester (173 mg; 0.34 mmol) was dissolved in ethanol (15mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reactionmixture was stirred for 16 h. acidified with 1 N aqueous hydrochloricacid and extracted with ethyl acetate. The organic phase was dried andevaporated to dryness. Yield: 107 mg; 66%. HPLC-MS: m/z: 482.0 (M+H)+;Rt: 1.62 min.

Example 46_(—{)4-[3-Cyclopropylmethoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid

Step A:{4-[3-Cyclopropylmethoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester

The title product was prepared from[4-(3-Bromo-5-cyclopropylmethoxy-phenyl-sulfanyl)-2-methyl-phenoxy]-aceticacid ethyl ester (250 mg; 0.55 mmol) and 4-prop-2-ynyl-morpholine (208mg; 1.7 mmol) applying the procedure described for{4-[3-[2-(4-Chlorophenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester. The crude product was purified by preparative HPLC(method B). Yield: 205 mg; 75%. HPLC-MS: m/z: 496.1 (M+H)+; Rt: 2.04min.

Step B:{4-[3-Cyclopropylmethoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid

{4-[3-Cyclopropylmethoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester (205 mg; 0.41 mmol) was dissolved in ethanol (15 mL),and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixturewas stirred for 16 h. acidified with 1 N aqueous hydrochloric acid andextracted with ethyl acetate. The organic phase was dried and evaporatedto dryness. Yield: 160 mg; 83%. HPLC-MS: m/z: 468.1 (M+H)+; Rt: 1.78min.

Example 47{4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2,5-dimethyl-phenoxy}-aceticacid

Step A:{4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2,5-dimethyl-phenoxy}-aceticacid ethyl ester

The title product was prepared from[4-(3-Bromo-5-isobutoxy-phenylsulfanyl)-2,5-dimethyl-phenoxy]-aceticacid ethyl ester (400 mg; 0.86 mmol) and 4-prop-2-ynyl-morpholine

(321.3 mg; 2.6 mmol) applying the procedure described for{4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester. The crude product was purified by preparative HPLC(method B). Yield: 350 mg; 80%. HPLC-MS: m/z: 512.2 (M+H)+; Rt: 2.09min.

Step B:{4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2,5-dimethyl-phenoxy}-aceticacid

{4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2,5-dimethyl-phenoxy}-aceticacid ethyl ester (350 mg; 0.68 mmol) was dissolved in ethanol (15 mL),and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixturewas stirred for 16 h. acidified with 1 N aqueous hydrochloric acid andextracted with ethyl acetate. The organic phase was dried and evaporatedto dryness and purified by prep HPLC (method B). Yield: 250 mg; 76%.HPLC-MS: m/z: 484.6 (M+H)+; Rt: 1.87 min.

Example 48{4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenoxy]-2-methyl-phenoxy}-aceticacid

Step A:{4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenoxy]-2-methyl-phenoxy}-aceticacid ethyl ester

The title product was prepared from[4-(3-Bromo-5-isobutoxy-phenylsulfanyl)-2,5-dimethyl-phenoxy]-aceticacid ethyl ester (300 mg; 0.71 mmol) and 4-prop-2-ynyl-morpholine

(266.1 mg; 2.1 mmol) applying the procedure described for{4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid ethyl ester. The crude product was purified by preparative HPLC(method B). Yield: 260 mg; 79%. HPLC-MS: m/z: 468.7 (M+H)+; Rt: 1.94 min

Step B:{4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenoxy]-2-methyl-phenoxy}-aceticacid

{4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenoxy]-2-methyl-phenoxy}-aceticacid ethyl ester (260 mg; 0.56 mmol) was dissolved in ethanol (15 mL),and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixturewas stirred for 16 h. acidified with 1 N aqueous hydrochloric acid andextracted with ethyl acetate. The organic phase was dried and evaporatedto dryness and purified by prep HPLC (method B). Yield: 180 mg; 72%.HPLC-MS: m/z: 454.6 (M+H)+; Rt: 1.77 min. δ_(H)(400 MHz; CDCl₃) 1.01 (d,6H), 2.02-2.10 (m, 1H), 2.28 (s, 3H), 3.10-3.55 (m, 4H), 3.68 (d, 2H),3.93-4.07 (m, 4H), 4.10 (s, 2H), 4.67 (s, 2H), 6.47 (m, 1H), 6.57-6.59(m, 1H), 6.66-6.69 (m, 1H), 6.71 (d, 1H), 6.79 (dd, 1H), 6.86 (d, 1H).

Pharmacological Methods In Vitro PPAR-δ Activation Activity

The PPAR transient transactivation assay is based on transienttransfection into human HEK293 cells of two plasmids encoding a chimerictest protein and a reporter protein respectively. The chimeric testprotein is a fusion of the DNA binding domain (DBD) from the yeast GAL4transcription factor to the ligand binding domain (LBD) of the humanPPAR proteins. The PPAR-LBD moiety harbored in addition to the ligandbinding pocket also the native activation domain (activating function2=AF2) allowing the fusion protein to function as a PPAR liganddependent transcription factor. The GAL4 DBD will direct the chimericprotein to bind only to Gal4 enhancers (of which none existed in HEK293cells). The reporter plasmid contained a Gal4 enhancer driving theexpression of the firefly luciferase protein. After transfection, HEK293cells expressed the GAL4-DBD-PPAR-LBD fusion protein. The fusion proteinwill in turn bind to the Gal4 enhancer controlling the luciferaseexpression, and do nothing in the absence of ligand. Upon addition tothe cells of a PPAR ligand luciferase protein will be produced inamounts corresponding to the activation of the PPAR protein. The amountof luciferase protein is measured by light emission after addition ofthe appropriate substrate.

Cell Culture and Transfection

HEK293 cells were grown in DMEM+10% FCS. Cells were seeded in 96-wellplates the day before transfection to give a confluency of 50-80% attransfection. A total of 0.8 μg DNA containing 0.64 μg pM1α/γLBD, 0.1 μgpCMVβGal, 0.08 μg pGL2(Gal4)₅ and 0.02 μg pADVANTAGE was transfected perwell using FuGene transfection reagent according to the manufacturersinstructions (Roche). Cells were allowed to express protein for 48 hfollowed by addition of compound.

Plasmids: Human PPAR-δ was obtained by PCR amplification using cDNAsynthesized by reverse transcription of mRNA from human liver, adiposetissue and plancenta respectively. Amplified cDNAs were cloned intopCR2.1 and sequenced. The ligand binding domain (LBD) of each PPARisoform was generated by PCR (PPARδ: aa 128-C-terminus) and fused to theDNA binding domain (DBD) of the yeast transcription factor GAL4 bysubcloning fragments in frame into the vector pM1 (Sadowski et al.(1992), Gene 118, 137) generating the plasmids pM1αLBD, pM1γLBD andpM1δ. Ensuing fusions were verified by sequencing. The reporter wasconstructed by inserting an oligonucleotide encoding five repeats of theGAL4 recognition sequence (5×CGGAGTACTGTCCTCCG(AG)) (Webster et al.(1988), Nucleic Acids Res. 16, 8192) into the vector pGL2 promotor(Promega) generating the plasmid pGL2(GAL4)₅. pCMVβGal was purchasedfrom Clontech and pADVANTAGE was purchased from Promega.

In Vitro Transactivation Assay

Compounds: All compounds were dissolved in DMSO and diluted 1:1000 uponaddition to the cells. Compounds were tested in quadruple inconcentrations ranging from 0.001 to 300 μM. Cells were treated withcompound for 24 h followed by luciferase assay. Each compound was testedin at least two separate experiments.

Luciferase assay: Medium including test compound was aspirated and 100μl PBS incl. 1 mM Mg++ and Ca++ were added to each well. The luciferaseassay was performed using the LucLite kit according to themanufacturer's instructions (Packard Instruments). Light emission wasquantified by counting on a Packard LumiCounter. To measureβ-galactosidase activity 25 μl supernatant from each transfection lysatewas transferred to a new microplate. β-Galactosidase assays wereperformed in the microwell plates using a kit from Promega and read in aLabsystems Ascent Multiscan reader. The β-galactosidase data were usedto normalize (transfection efficiency, cell growth etc.) the luciferasedata.

Statistical Methods

The activity of a compound is calculated as fold induction compared toan untreated sample. For each compound the efficacy (maximal activity)is given as a relative activity compared to Wy14,643 for PPARα,Rosiglitazone for PPARγ and Carbacyclin for PPARδ. The EC50 is theconcentration giving 50% of maximal observed activity. EC50 values werecalculated via non-linear regression using GraphPad PRISM 3.02 (GraphPadSoftware, San Diego, Calif.).

While the invention has been described and illustrated with reference tocertain preferred embodiments thereof, those skilled in the art willappreciate that various changes, modifications, and substitutions can bemade therein without departing from the spirit and scope of the presentinvention. For example, effective dosages other than the preferreddosages as set forth herein may be applicable as a consequence ofvariations in the responsiveness of the mammal being treated for PPAR-δmediated disease(s). Likewise, the specific pharmacological responsesobserved may vary according to and depending on the particular activecompound selected or whether there are present pharmaceutical carriers,as well as the type of formulation and mode of administration employed,and such expected variations or differences in the results arecontemplated in accordance with the objects and practices of the presentinvention. Accordingly, the invention is not to be limited as by theappended claims.

The features disclosed in the foregoing description and/or in the claimsmay both separately ans in any combination thereof be material forrealising the invention in diverse forms thereof.

PREFERRED FEATURES OF THE INVENTION

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

X is selected from O, S, OCH₂, and SCH₂;

X¹ is O or S;

R¹ is selected from H, C₁₋₈ alkyl, C₂₋₈ alkenyl, aryl, heteroaryl, C₃₋₁₀cycloalkyl, and a heterocyclyl, wherein each R¹ group is substitutedwith 0-4 R^(1a);

R^(1a), at each occurrence, is selected from S substituted with 0-1R^(1b), O substituted with 0-1 R^(1b), halogen, NH₂ substituted with 0-2R^(1b), —CN, NO₂, C₁₋₆alkyl substituted with 0-3 R^(1b), C₂₋₆ alkenylsubstituted with 0-2 R^(1b), C₂₋₆alkynyl substituted with 0-2 R^(1b),aryl substituted with 0-2 R^(1b), heteroaryl substituted with 0-2R^(1b), C₃₋₁₀ cycloalkyl substituted with 0-2 R^(1b), and heterocyclesubstituted with 0-2 R^(1b);

R^(1b), at each occurrence, is selected from S substituted with 0-1R^(1c), O substituted with 0-1 R^(1c), halogen, methanesulfonyl, NH₂substituted with 0-2 R^(1c), —CN, NO₂, C₁₋₆ alkyl substituted with 0-3R^(1c), C₂₋₆alkenyl substituted with 0-2 R^(1c), aryl substituted with0-2 R^(1c), heteroaryl substituted with 0-2 R^(1c), C₃₋₁₀ cycloalkylsubstituted with 0-2 R^(1c), and a heterocycle substituted with 0-2R^(1c);

R^(1c), at each occurrence, is selected from S substituted with 0-1R^(1d), O substituted with 0-1 R^(1d), halogen, NH₂ substituted with 0-2R^(1d), —CN, NO₂, C₁₋₆alkyl substituted with 0-2 R^(1d), C₂₋₆ alkenylsubstituted with 0-2 R^(1d), aryl substituted with 0-2 R^(1d),heteroaryl substituted with 0-2 R^(1d), C₃₋₁₀ cycloalkyl substitutedwith 0-2 R^(1d), and a heterocycle substituted with 0-2 R^(1d);

R^(1d), at each occurrence, is selected from OH, SH, S, O, halogen, NH₂,—CN, NO₂, C₁₋₆ alkyl, C₂₋₆alkenyl, aryl, CF₃, and OCF₃;

R² is selected from —C≡C—R^(2a), —CH═CH—R^(2a), aryl substituted with0-3 R^(2a), and heteroaryl substituted with 0-3 R^(2a);

R^(2a), at each occurrence, is selected from S substituted with 0-1R^(2b), O substituted with 0-1 R^(2b), halogen, NH₂ substituted with 0-2R^(2b), —CN, NO₂, C₁₋₆ alkyl substituted with 0-2 R^(2b), C₂₋₆ alkenylsubstituted with 0-2 R^(2b), aryl substituted with 0-2 R^(2b),heteroaryl substituted with 0-2 R^(2b), C₃₋₁₀ cycloalkyl substitutedwith 0-2 R^(2b), and a heterocycle substituted with 0-2;

R^(2b), at each occurrence, is selected from S substituted with 0-1R^(2c), O substituted with 0-1 R^(2c), halogen, methanesulfonyl, NH₂substituted with 0-2 R^(2c), —CN, NO₂, C₁₋₆ alkyl substituted with 0-2R^(2c), C₂₋₆alkenyl substituted with 0-2 R^(2c), aryl substituted with0-2 R^(2c), heteroaryl substituted with 0-2 R^(2c), C₃₋₁₀ cycloalkylsubstituted with 0-2 R^(2c), and a heterocycle substituted with 0-2R^(2c);

R^(2c), at each occurrence, is selected from S substituted with 0-1R^(2d), O substituted with 0-1 R^(2d), halogen, NH₂ substituted with 0-2R^(2d), —CN, NO₂, C₁₋₆alkyl substituted with 0-2 R^(2d), C₂₋₆ alkenylsubstituted with 0-2 R^(2d), aryl substituted with 0-2 R^(2d),heteroaryl substituted with 0-2 R^(2d), C₃₋₁₀ cycloalkyl substitutedwith 0-2 R^(2d), and a heterocycle substituted with 0-2 R^(2d)

R^(2d), at each occurrence, is selected from OH, SH, S, O, halogen, NH₂,—CN, NO₂, C₁₋₆ alkyl, C₂₋₆alkenyl, aryl, CF₃, and OCF₃;

R³ is selected from halogen and C₁₋₆alkyl substituted with 0-2 R^(3a);

R^(3a), at each occurrence, is selected from OH, O, S, halogen, C(O)NH₂,C(O)NH—C₁₋₄ alkyl, and C(O)N(C₁₋₄ alkyl)₂;

alternatively, R³ and R^(5e) combine to form a 5, 6, or 7 membered ringconsisting of carbon atoms and 0-2 heteroatoms selected from O, N, andS(O)₀₋₂ and there are 0-2 ring double bonds in the bridging portionformed by R³ and R^(5e);

R^(4a), at each occurrence, is selected from H, halogen, and C₁₋₆alkylsubstituted with 0-2 R^(4d);

R^(4d), at each occurrence, is selected from OH, O, halogen, NH₂,NH—C₁₋₄ alkyl, and N(C₁₋₄ alkyl)₂;

R^(4b), at each occurrence, is selected from H, halogen, and C₁₋₆alkylsubstituted with 0-2 R^(4e);

R^(4e), at each occurrence, is selected from OH, O, halogen, NH₂,NH—C₁₋₁₄ alkyl, and N(C₁₋₄ alkyl)₂;

R^(4c), at each occurrence, is selected from H, halogen, and C₁₋₆ alkylsubstituted with 0-2 R^(4f);

R^(4f), at each occurrence, is selected from OH, O, halogen, NH₂,NH—C₁₋₄ alkyl, and N(C₁₋₄ alkyl)₂;

R^(5a), at each occurrence, is selected from H, halogen, CH₃, and CH₂CH₃;

R^(5b), at each occurrence, is selected from H, halogen, CH₃, and CH₂CH₃;

R^(5c), at each occurrence, is selected from H, halogen, CH₃, and CH₂CH₃;

R^(5d), at each occurrence, is selected from H, halogen, CH₃, and CH₂CH₃; and,

R^(5e), at each occurrence, is selected from H, halogen, CH₃, and CH₂CH₃.

2. A compound of clause 1 wherein:

X is selected from O, S, OCH₂, and SCH₂;

X¹ is O or S;

R¹ is selected from H, C₁₋₈ alkyl, C₂₋₈ alkenyl, aryl, 5-10 memberedheteroaryl consisting of carbon atoms and 1-4 heteroatoms selected fromO, N, and S(O)₀₋₂, C₃₋₁₀ cycloalkyl, and a 3-8 membered heterocycleconsisting of carbon atoms and 1-3 heteroatoms selected from O, N, andS(O)₀₋₂, wherein each R¹ group is substituted with 0-4 R^(1a);

R^(1a), at each occurrence, is selected from OH substituted with 0-1R^(1b), SH substituted with 0-1 R^(1b), S, O, halogen, NH₂ substitutedwith 0-2 R^(1b), —CN, NO₂, C₁₋₆ alkyl substituted with 0-3 R^(1b),C₂₋₆alkenyl substituted with 0-2 R^(1b), C₂₋₆alkynyl substituted with0-2 R^(1b), aryl substituted with 0-2 R^(1b), 5-10 membered heteroarylsubstituted with 0-2 R^(1b) and consisting of carbon atoms and 1-4heteroatoms selected from O, N, and S(O)₀₋₂, C₃₋₁₀ cycloalkylsubstituted with 0-2 R^(1b), and a 3-8 membered heterocycle substitutedwith 0-2 R^(1b) and consisting of carbon atoms and 1-3 heteroatomsselected from O, N, and S(O)₀₋₂;

R^(1b), at each occurrence, is selected from OH substituted with 0-1R^(1c), SH substituted with 0-1 R^(1c), S, O, halogen, methanesulfonyl,NH₂ substituted with 0-2 R^(1c), —CN, NO₂, C₁₋₆ alkyl substituted with0-3 R^(1c), C₂₋₆alkenyl substituted with 0-2 R^(1c), aryl substitutedwith 0-2 R^(1c), 5-10 membered heteroaryl substituted with 0-2 R^(1c)and consisting of carbon atoms and 1-4 heteroatoms selected from O, N,and S(O)₀₋₂, C₃₋₁₀ cycloalkyl substituted with 0-2 R^(1c), and a 3-8membered heterocycle substituted with 0-2 R^(1c) and consisting ofcarbon atoms and 1-3 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(1c), at each occurrence, is selected from OH substituted with 0-1R^(1d), SH substituted with 0-1 R^(1d), S, O, halogen, NH₂ substitutedwith 0-2 R^(1d), —CN, NO₂, C₁₋₆alkyl substituted with 0-2 R^(1d),C₂₋₆alkenyl substituted with 0-2 R^(1d), aryl substituted with 0-2R^(1d), 5-10 membered heteroaryl substituted with 0-2 R^(1d) andconsisting of carbon atoms and 1-4 heteroatoms selected from O, N, andS(O)₀₋₂, C₃₋₁₀ cycloalkyl substituted with 0-2 R^(1d), and a 3-8membered heterocycle substituted with 0-2 R^(1d) and consisting ofcarbon atoms and 1-3 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(1d), at each occurrence, is selected from OH, SH, S, O, halogen, NH₂,—CN, NO₂, C₁₋₆ alkyl, C₂₋₆alkenyl, aryl, CF₃, and OCF₃;

R² is selected from —C≡C—R^(2a), —CH═CH—R^(2a) substituted with 0-2R^(2a), aryl substituted with 0-3 R^(2a), and 5-10 membered heteroarylsubstituted with 0-3 R^(2a) and consisting of carbon atoms and 1-4heteroatoms selected from O, N, and S(O)₀₋₂;

R^(2a), at each occurrence, is selected from OH substituted with 0-1R^(2b), SH substituted with 0-1 R^(2b), S, O, halogen, NH₂ substitutedwith 0-2 R^(2b), —CN, NO₂, C₁₋₆ alkyl substituted with 0-2 R^(2b),C₂₋₆alkenyl substituted with 0-2 R^(2b), aryl substituted with 0-2R^(2b), 5-10 membered heteroaryl substituted with 0-2 R^(2b) andconsisting of carbon atoms and 1-4 heteroatoms selected from O, N, andS(O)₀₋₂, C₃₋₁₀ cycloalkyl substituted with 0-2 R^(2b), and a 3-8membered heterocycle substituted with 0-2 R^(2b) and consisting ofcarbon atoms and 1-3 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(2b), at each occurrence, is selected from OH substituted with 0-1R^(2c), SH substituted with 0-1 R^(2c), S, O substituted with 0-1R^(2c), halogen, methanesulfonyl, NH₂ substituted with 0-2 R^(2c), —CN,NO₂, C₁₋₆ alkyl substituted with 0-2 R^(2c), C₂₋₆alkenyl substitutedwith 0-2 R^(2c), aryl substituted with 0-2 R^(2c), 5-10 memberedheteroaryl substituted with 0-2 R^(2c) and consisting of carbon atomsand 1-4 heteroatoms selected from O, N, and S(O)₀₋₂, C₃₋₁₀ cycloalkylsubstituted with 0-2 R^(2c), and a 3-8 membered heterocycle substitutedwith 0-2 R^(2c) and consisting of carbon atoms and 1-3 heteroatomsselected from O, N, and S(O)₀₋₂;

R^(2c), at each occurrence, is selected from OH substituted with 0-1R^(2d), SH substituted with 0-1 R^(2d), S, O, halogen, NH₂ substitutedwith 0-2 R^(2d), —CN, NO₂, C₁₋₆alkyl substituted with 0-2 R^(2d),C₂₋₆alkenyl substituted with 0-2 R^(2d), aryl substituted with 0-2R^(2d), 5-10 membered heteroaryl substituted with 0-2 R^(2d) andconsisting of carbon atoms and 1-4 heteroatoms selected from O, N, andS(O)₀₋₂, C₃₋₁₀ cycloalkyl substituted with 0-2 R^(2d), and a 3-8membered heterocycle substituted with 0-2 R^(2d) and consisting ofcarbon atoms and 1-3 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(2d), at each occurrence, is selected from OH, SH, S, O, halogen, NH₂,—CN, NO₂, C₁₋₆ alkyl, C₂₋₆alkenyl, aryl, CF₃, and OCF₃;

R³ is selected from halogen and C₁₋₆ alkyl substituted with 0-2 R^(3a);

R^(3a), at each occurrence, is selected from OH, O, S, halogen, C(O)NH₂,C(O)NH—C₁₋₄ alkyl, and C(O)N(C₁₋₄ alkyl)₂;

alternatively, R³ and R^(5e) combine to form a 5, 6, or 7 membered ringconsisting of carbon atoms and 0-2 heteroatoms selected from O, N, andS(O)₀₋₂ and there are 0-2 ring double bonds in the bridging portionformed by R³ and R^(5e);

R^(4a), at each occurrence, is selected from H, halogen, and C₁₋₆ alkylsubstituted with 0-2 R^(4d);

R^(4d), at each occurrence, is selected from OH, O, halogen, NH₂,NH—C₁₋₄ alkyl, and N(C₁₋₄ alkyl)₂;

R^(4b), at each occurrence, is selected from H, halogen, and C₁₋₆alkylsubstituted with 0-2 R^(4e);

R^(4e), at each occurrence, is selected from OH, O, halogen, NH₂,NH—C₁₋₄ alkyl, and N(C₁₋₄alkyl)₂;

R^(4c), at each occurrence, is selected from H, halogen, and C₁₋₆alkylsubstituted with 0-2 R^(4f);

R^(4f), at each occurrence, is selected from OH, O, halogen, NH₂,NH—C₁₋₄ alkyl, and N(C₁₋₄ alkyl)₂;

R^(5a), at each occurrence, is selected from H, halogen, CH₃, and CH₂CH₃;

R^(5b), at each occurrence, is selected from H, halogen, CH₃, and CH₂CH₃;

R^(5c), at each occurrence, is selected from H, halogen, CH₃, and CH₂CH₃;

R^(5d), at each occurrence, is selected from H, halogen, CH₃, and CH₂CH₃; and,

R^(5e), at each occurrence, is selected from H, halogen, CH₃, and CH₂CH₃.

3. A compound of clause 1 or 2 wherein:

X is selected from O, S, OCH₂, and SCH₂;

X¹ is O or S;

R¹ is selected from H, C₁₋₈ alkyl, C₂₋₈ alkenyl, aryl, 5-10 memberedheteroaryl consisting of carbon atoms and 1-4 heteroatoms selected fromO, N, and S(O)₀₋₂, C₃₋₁₀ cycloalkyl, and a 3-8 membered heterocycleconsisting of carbon atoms and 1-3 heteroatoms selected from O, N, andS(O)₀₋₂, wherein each R¹ group is substituted with 0-4 R^(1a);

R^(1a), at each occurrence, is selected from OH substituted with 0-1R^(1b), SH substituted with 0-1 R^(1b), S, O, halogen, NH₂ substitutedwith 0-2 R^(1b), —CN, NO₂, C₁₋₆alkyl substituted with 0-2 R^(1b),C₂₋₆alkenyl substituted with 0-2 R^(1b), C₂₋₆alkynyl substituted with0-2 R^(1b), aryl substituted with 0-2 R^(1b), 5-10 membered heteroarylsubstituted with 0-2 R^(1b) and consisting of carbon atoms and 1-4heteroatoms selected from O, N, and S(O)₀₋₂, C₃₋₁₀ cycloalkylsubstituted with 0-2 R^(1b), and a 3-8 membered heterocycle substitutedwith 0-2 R^(1b) and consisting of carbon atoms and 1-3 heteroatomsselected from O, N, and S(O)₀₋₂;

R^(1b), at each occurrence, is selected from OH substituted with 0-1R^(1c), SH substituted with 0-1 R^(1c), S, O, halogen, NH₂ substitutedwith 0-2 R^(1c), —CN, NO₂, C₁₋₆ alkyl substituted with 0-2 R^(1c),C₂₋₆alkenyl substituted with 0-2 R^(1c), aryl substituted with 0-2R^(1c), 5-10 membered heteroaryl substituted with 0-2 R^(1c) andconsisting of carbon atoms and 1-4 heteroatoms selected from O, N, andS(O)₀₋₂, C₃₋₁₀ cycloalkyl substituted with 0-2 R^(1c), and a 3-8membered heterocycle substituted with 0-2 R^(1c) and consisting ofcarbon atoms and 1-3 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(1c), at each occurrence, is selected from OH substituted with 0-1R^(1d), SH substituted with 0-1 R^(1d), S, O, halogen, NH₂ substitutedwith 0-2 R^(1d), —CN, NO₂, C₁₋₆alkyl substituted with 0-2 R^(1d),C₂₋₆alkenyl substituted with 0-2 R^(1d), aryl substituted with 0-2R^(1d), 5-10 membered heteroaryl substituted with 0-2 R^(1d) andconsisting of carbon atoms and 1-4 heteroatoms selected from O, N, andS(O)₀₋₂, C₃₋₁₀ cycloalkyl substituted with 0-2 R^(1d), and a 3-8membered heterocycle substituted with 0-2 R^(1d) and consisting ofcarbon atoms and 1-3 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(1d), at each occurrence, is selected from OH, SH, S, O, halogen, NH₂,—CN, NO₂, C₁₋₆ alkyl, C₂₋₆alkenyl, aryl, CF₃, and OCF₃;

R² is selected from —C≡C—R^(2a), —CH═CH—R^(2a) substituted with 0-2R^(2a), aryl substituted with 0-3 R^(2a), and 5-10 membered heteroarylsubstituted with 0-3 R^(2a) and consisting of carbon atoms and 1-4heteroatoms selected from O, N, and S(O)₀₋₂;

R^(2a), at each occurrence, is selected from OH substituted with 0-1R^(2b), SH substituted with 0-1 R^(2b), S, O, halogen, NH₂ substitutedwith 0-2 R^(2b), —CN, NO₂, C₁₋₆ alkyl substituted with 0-2 R^(2b),C₂₋₆alkenyl substituted with 0-2 R^(2b), aryl substituted with 0-2R^(2b), 5-10 membered heteroaryl substituted with 0-2 R^(2b) andconsisting of carbon atoms and 1-4 heteroatoms selected from O, N, andS(O)₀₋₂, C₃₋₁₀ cycloalkyl substituted with 0-2 R^(2b), and a 3-8membered heterocycle substituted with 0-2 R^(2b) and consisting ofcarbon atoms and 1-3 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(2b), at each occurrence, is selected from OH substituted with 0-1R^(2c), SH substituted with 0-1 R^(2c), S, O, halogen, NH₂ substitutedwith 0-2 R^(2c), —CN, NO₂, C₁₋₆ alkyl substituted with 0-2 R^(2c),C₂₋₆alkenyl substituted with 0-2 R^(2c), aryl substituted with 0-2R^(2c), 5-10 membered heteroaryl substituted with 0-2 R^(2c) andconsisting of carbon atoms and 1-4 heteroatoms selected from O, N, andS(O)₀₋₂, C₃₋₁₀ cycloalkyl substituted with 0-2 R^(2c), and a 3-8membered heterocycle substituted with 0-2 R^(2c) and consisting ofcarbon atoms and 1-3 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(2c), at each occurrence, is selected from OH substituted with 0-1R^(2d), SH substituted with 0-1 R^(2d), S, O, halogen, NH₂ substitutedwith 0-2 R^(2d), —CN, NO₂, C₁₋₆alkyl substituted with 0-2 R^(2d),C₂₋₆alkenyl substituted with 0-2 R^(2d), aryl substituted with 0-2R^(2d), 5-10 membered heteroaryl substituted with 0-2 R^(2d) andconsisting of carbon atoms and 1-4 heteroatoms selected from O, N, andS(O)₀₋₂, C₃₋₁₀ cycloalkyl substituted with 0-2 R^(2d), and a 3-8membered heterocycle substituted with 0-2 R^(2d) and consisting ofcarbon atoms and 1-3 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(2d), at each occurrence, is selected from OH, SH, S, O, halogen, NH₂,—CN, NO₂, C₁₋₆ alkyl, C₂₋₆alkenyl, aryl, CF₃, and OCF₃;

R³ is selected from halogen and C₁₋₆ alkyl substituted with 0-2 R^(3a);

R^(3a), at each occurrence, is selected from OH, O, S, halogen, C(O)NH₂,C(O)NH—C₁₋₄ alkyl, and C(O)N(C₁₋₄ alkyl)₂;

alternatively, R³ and R^(5e) combine to form a 5, 6, or 7 membered ringconsisting of carbon atoms and 0-2 heteroatoms selected from O, N, andS(O)₀₋₂ and there are 0-2 ring double bonds in the bridging portionformed by R³ and R^(5e);

R^(4a), at each occurrence, is selected from H, halogen, and C₁₋₆ alkylsubstituted with 0-2 R^(4d);

R^(4d), at each occurrence, is selected from OH, O, halogen, NH₂,NH—C₁₋₄ alkyl, and N(C₁₋₄ alkyl)₂;

R^(4b), at each occurrence, is selected from H, halogen, and C₁₋₆ alkylsubstituted with 0-2 R^(4e);

R^(4e), at each occurrence, is selected from OH, O, halogen, NH₂,NH—C₁₋₄alkyl, and N(C₁₋₄ alkyl)₂;

R^(4c), at each occurrence, is selected from H, halogen, and C₁₋₆ alkylsubstituted with 0-2 R^(4f);

R^(4f), at each occurrence, is selected from OH, O, halogen, NH₂,NH—C₁₋₄ alkyl, and N(C₁₋₄ alkyl)₂;

R^(5a), at each occurrence, is selected from H, halogen, CH₃, and CH₂CH₃;

R^(5b), at each occurrence, is selected from H, halogen, CH₃, and CH₂CH₃;

R^(5c), at each occurrence, is selected from H, halogen, CH₃, and CH₂CH₃;

R^(5d), at each occurrence, is selected from H, halogen, CH₃, and CH₂CH₃; and,

R^(5e), at each occurrence, is selected from H, halogen, CH₃, and CH₂CH₃.

4. A compound of any of the preceding clauses 1-3, wherein the compoundis of formula Ia:

or a pharmaceutically acceptable salt thereof.

5. A compound of clause 1, wherein the compound is of formula II:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, C₁₋₈ alkyl, heteroaryl, and C₃₋₁₀ cycloalkyl, wherein each R¹group is substituted with 0-4 R^(1a);

R^(1a), at each occurrence, is selected from C₁₋₆ alkyl substituted with0-3 R^(1b); C₂₋₆alkynyl substituted with 0-2 R^(1b); aryl substitutedwith 0-2 R^(1b), heteroaryl substituted with 0-2 R^(1b), C₃₋₁₀cycloalkyl substituted with 0-2 R^(1b), and a heterocycle substitutedwith 0-2 R^(1b);

R^(1b), at each occurrence, is selected from OH substituted with 0-1R^(1c), SH substituted with 0-1 R^(1c), Cl, F, NH₂ substituted with 0-2R^(1c), —CN, NO₂, methanesulfonyl, C₁₋₄ alkyl substituted with 0-3R^(1c), C₂₋₄alkenyl substituted with 0-2 R^(1c), aryl substituted with0-2 R^(1c), heteroaryl substituted with 0-2 R^(1c), C₃₋₆cycloalkylsubstituted with 0-2 R^(1c), and a heterocycle substituted with 0-2R^(1c);

R^(1c), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, and C₂₋₄alkenyl, aryl substituted with 0-2 R^(1d),heteroaryl substituted with 0-2 R^(1d) and, C₃₋₆cycloalkyl substitutedwith 0-2 R^(1d), and a heterocycle substituted with 0-2 R^(1d);

R^(1d), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, and C₂₋₄alkenyl;

R^(2a) is selected from C₁₋₆ alkyl substituted with 0-2 R^(2b), arylsubstituted with 0-2 R^(2b), and heteroaryl substituted with 0-2 R^(2b);

R^(2b), at each occurrence, is selected from OH substituted with 0-1R^(2c), SH substituted with 0-1 R^(2c), Cl, F, NH₂ substituted with 0-2R^(2c), —CN, NO₂, methanesulfonyl, C₁₋₄ alkyl substituted with 0-2R^(2c), C₂₋₄alkenyl substituted with 0-2 R^(2c), aryl substituted with0-2 R^(2c), heteroaryl substituted with 0-2 R^(2c), C₃₋₆cycloalkylsubstituted with 0-2 R^(2c), and a heterocycle substituted with 0-2R^(2c);

R^(2c), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, C₂₋₄ alkenyl, aryl substituted with 0-2 R^(2d), andheteroaryl substituted with 0-2 R^(2d);

R^(2d), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, and C₂₋₄ alkenyl;

R³ is selected from Cl, F, CH₃, and CH₂ CH₃;

alternatively, R³ and R^(5e) combine to form a 5, 6, or 7 membered ringconsisting of carbon atoms and 0-2 heteroatoms selected from O, N, andS(O)₀₋₂ and there are 0-2 ring double bonds in the bridging portionformed by R³ and R^(5e);

R^(4a), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(4b), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(4c), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(5a), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(5b), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(5c), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(5d), at each occurrence, is selected from H, Cl, F, and CH₃; and,

R^(5e), at each occurrence, is selected from H, Cl, F, and CH₃.

6. A compound of clause 5 wherein:

R¹ is H, C₁₋₈ alkyl, 5-10 membered heteroaryl consisting of carbon atomsand 1-4 heteroatoms selected from O, N, and S(O)₀₋₂, and C₃₋₁₀cycloalkyl, wherein each R¹ group is substituted with 0-4 R^(1a);

R^(1a), at each occurrence, is selected from C₁₋₆alkyl substituted with0-3 R^(1b); C₂₋₆alkynyl substituted with 0-2 R^(1b); aryl substitutedwith 0-2 R^(1b), 5-10 membered heteroaryl substituted with 0-2 R^(1b)and consisting of carbon atoms and 1-4 heteroatoms selected from O, N,and S(O)₀₋₂, C₃₋₁₀ cycloalkyl substituted with 0-2 R^(1b), and a 3-8membered heterocycle substituted with 0-2 R^(1b) and consisting ofcarbon atoms and 1-2 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(1b), at each occurrence, is selected from OH substituted with 0-1R^(1c), SH substituted with 0-1 R^(1c), Cl, F, NH₂ substituted with 0-2R^(1c), —CN, NO₂, methanesulfonyl, C₁₋₄alkyl substituted with 0-3R^(1c), C₂₋₄alkenyl substituted with 0-2 R^(1c), aryl substituted with0-2 R^(1c), 5-10 membered heteroaryl substituted with 0-2 R^(1c) andconsisting of carbon atoms and 1-4 heteroatoms selected from O, N, andS(O)₀₋₂, C₃₋₆cycloalkyl substituted with 0-2 R^(1c), and a 3-6 memberedheterocycle substituted with 0-2 R^(1c) and consisting of carbon atomsand 1-2 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(1c), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, and C₂₋₄alkenyl, aryl substituted with 0-2 R^(1d), 5-10membered heteroaryl substituted with 0-2 R^(1d) and consisting of carbonatoms and 1-4 heteroatoms selected from O, N, and S(O)₀₋₂, C₃₋₆cycloalkyl substituted with 0-2 R^(1d), and a 3-6 membered heterocyclesubstituted with 0-2 R^(1d) and consisting of carbon atoms and 1-2heteroatoms selected from O, N, and S(O)₀₋₂;

R^(1d), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, and C₂₋₄alkenyl;

R^(2a) is selected from C₁₋₆ alkyl substituted with 0-2 R^(2b), arylsubstituted with 0-2 R^(2b), and 5-10 membered heteroaryl substitutedwith 0-2 R^(2b) and consisting of carbon atoms and 1-4 heteroatomsselected from O, N, and S(O)₀₋₂;

R^(2b), at each occurrence, is selected from OH substituted with 0-1R^(2c), SH substituted with 0-1 R^(2c), Cl, F, NH₂ substituted with 0-2R^(2c), —CN, NO₂, methanesulfonyl, C₁₋₄ alkyl substituted with 0-2R^(2c), C₂₋₄alkenyl substituted with 0-2 R^(2c), aryl substituted with0-2 R^(2c), 5-10 membered heteroaryl substituted with 0-2 R^(2c) andconsisting of carbon atoms and 1-4 heteroatoms selected from O, N, andS(O)₀₋₂, C₃₋₆cycloalkyl substituted with 0-2 R^(2c), and a 3-6 memberedheterocycle substituted with 0-2 R^(2c) and consisting of carbon atomsand 1-2 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(2c), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, C₂₋₄ alkenyl, aryl substituted with 0-2 R^(2d), and5-10 membered heteroaryl substituted with 0-2 R^(2d) and consisting ofcarbon atoms and 1-4 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(2d), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, and C₂₋₄ alkenyl;

R³ is selected from Cl, F, CH₃, and CH₂ CH₃;

alternatively, R³ and R^(5e) combine to form a 5, 6, or 7 membered ringconsisting of carbon atoms and 0-2 heteroatoms selected from O, N, andS(O)₀₋₂ and there are 0-2 ring double bonds in the bridging portionformed by R³ and R^(5e);

R^(4a), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(4b), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(4c), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(5a), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(5b), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(5c), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(5d), at each occurrence, is selected from H, Cl, F, and CH₃; and,

R^(5e), at each occurrence, is selected from H, Cl, F, and CH₃.

7. A compound of clause 5 or 6, wherein:

R¹ is H or C₁₋₄ alkyl substituted with 1-4 R^(1a);

R^(1a), at each occurrence, is selected from aryl substituted with 0-2R^(1b), 5-10 membered heteroaryl substituted with 0-2 R^(1b) andconsisting of carbon atoms and 1-4 heteroatoms selected from O, N, andS(O)₀₋₂, C₃₋₁₀ cycloalkyl substituted with 0-2 R^(1b), and a 3-8membered heterocycle substituted with 0-2 R^(1b) and consisting ofcarbon atoms and 1-2 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(1b), at each occurrence, is selected from OH substituted with 0-1R^(1c), SH substituted with 0-1 R^(1c), Cl, F, NH₂ substituted with 0-2R^(1c), —CN, NO₂, C₁₋₄ alkyl substituted with 0-2 R^(1c), C₂₋₄alkenylsubstituted with 0-2 R^(1c), aryl substituted with 0-2 R^(1c), 5-10membered heteroaryl substituted with 0-2 R^(1c) and consisting of carbonatoms and 1-4 heteroatoms selected from O, N, and S(O)₀₋₂,C₃₋₆cycloalkyl substituted with 0-2 R^(1c), and a 3-6 memberedheterocycle substituted with 0-2 R^(1c) and consisting of carbon atomsand 1-2 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(1c), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, and C₂₋₄alkenyl, aryl substituted with 0-2 R^(1d), 5-10membered heteroaryl substituted with 0-2 R^(1d) and consisting of carbonatoms and 1-4 heteroatoms selected from O, N, and S(O)₀₋₂, C₃₋₆cycloalkyl substituted with 0-2 R^(1d), and a 3-6 membered heterocyclesubstituted with 0-2 R^(1d) and consisting of carbon atoms and 1-2heteroatoms selected from O, N, and S(O)₀₋₂;

R^(1d), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, and C₂₋₄ alkenyl;

R^(2a) is selected from C₁₋₆ alkyl substituted with 0-2 R^(2b), arylsubstituted with 0-2 R^(2b), and 5-10 membered heteroaryl substitutedwith 0-2 R^(2b) and consisting of carbon atoms and 1-4 heteroatomsselected from O, N, and S(O)₀₋₂;

R^(2b), at each occurrence, is selected from OH substituted with 0-1R^(2c), SH substituted with 0-1 R^(2c), Cl, F, NH₂ substituted with 0-2R^(2c), —CN, NO₂, C₁₋₄ alkyl substituted with 0-2 R^(2c), C₂₋₄alkenylsubstituted with 0-2 R^(2c), aryl substituted with 0-2 R^(2c), 5-10membered heteroaryl substituted with 0-2 R^(2c) and consisting of carbonatoms and 1-4 heteroatoms selected from O, N, and S(O)₀₋₂,C₃₋₆cycloalkyl substituted with 0-2 R^(2c), and a 3-6 memberedheterocycle substituted with 0-2 R^(2c) and consisting of carbon atomsand 1-2 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(2c), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, C₂₋₄ alkenyl, aryl substituted with 0-2 R^(2d), and5-10 membered heteroaryl substituted with 0-2 R^(2d) and consisting ofcarbon atoms and 1-4 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(2d), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, and C₂₋₄alkenyl;

R³ is selected from Cl, F, CH₃, and CH₂ CH₃;

alternatively, R³ and R^(5e) combine to form a 5, 6, or 7 membered ringconsisting of carbon atoms and 0-2 heteroatoms selected from O, N, andS(O)₀₋₂ and there are 0-2 ring double bonds in the bridging portionformed by R³ and R^(5e);

R^(4a), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(4b), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(4c), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(5a), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(5b), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(5c), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(5d), at each occurrence, is selected from H, Cl, F, and CH₃; and,

R^(5e), at each occurrence, is selected from H, Cl, F, and CH₃.

8. A compound of clause 5, wherein the compound is of formula IIa:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, C₁₋₆ alkyl, aryl, heteroaryl, and C₃₋₁₀ cycloalkyl, whereineach R¹ group is substituted with 0-1 R^(1a);

R^(1a), at each occurrence, is selected from C₁₋₆ alkyl substituted with0-3 R^(1b); C₂₋₆alkynyl substituted with 0-2 R^(1b); aryl substitutedwith 0-2 R^(1b), heteroaryl substituted with 0-2 R^(1b) and,C₅₋₆cycloalkyl substituted with 0-2 R^(1b), and a heterocyclesubstituted with 0-2 R^(1b) and;

R^(1b), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, methanesulfonyl, C₁₋₄ alkyl substituted with 0-3 R^(1c),C₂₋₄alkenyl substituted with 0-2 R^(1c), aryl substituted with 0-2R^(1c), heteroaryl substituted with 0-2 R^(1c), C₅₋₆ cycloalkylsubstituted with 0-2 R^(1c), and a heterocycle substituted with 0-2R^(1c);

R^(1c), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, and C₂₋₄alkenyl, aryl substituted with 0-2 R^(1d),heteroaryl substituted with 0-2 R^(1d), C₅₋₆cycloalkyl substituted with0-2 R^(1d), and a heterocycle substituted with 0-2 R^(1d);

R^(1d), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, and C₂₋₄ alkenyl;

R^(2a) is selected from C₁₋₆ alkyl substituted with 0-2 R^(2b), arylsubstituted with 0-2 R^(2b), and heteroaryl substituted with 0-2 R^(2b);

R^(2b), at each occurrence, is selected from OH substituted with 0-1R^(2c), SH, Cl, F, NH₂, —CN, NO₂, methanesulfonyl, C₁₋₄ alkyl, C₂₋₄alkenyl, aryl, heteroaryl, C₅₋₆cycloalkyl, and a heterocycle;

R^(2c), at each occurrence, is C₁₋₄ alkyl;

R³ is selected from Cl, F, CH₃, and CH₂ CH₃; and,

alternatively, R³ and R^(5e) combine to form a 5, 6, or 7 membered ringconsisting of carbon atoms and 0-2 heteroatoms selected from O, N, andS(O)₀₋₂ and there are 0-2 ring double bonds in the bridging portionformed by R³ and R^(5e).

9. A compound of clause 8 wherein:

R¹ is H, C₁₋₆ alkyl, aryl, 5-6 membered heteroaryl consisting of carbonatoms and 1-4 heteroatoms selected from O, N, and S(O)₀₋₂, and C₃₋₁₀cycloalkyl, wherein each R¹ group is substituted with 0-1 R^(1a);

R^(1a), at each occurrence, is selected from C₁₋₆ alkyl substituted with0-3 R^(1b); C₂₋₆alkynyl substituted with 0-2 R^(1b); aryl substitutedwith 0-2 R^(1b), 5-6 membered heteroaryl substituted with 0-2 R^(1b) andconsisting of carbon atoms and 1-2 heteroatoms selected from O, N, andS(O)₀₋₂, C₅₋₆ cycloalkyl substituted with 0-2 R^(1b), and a 5-6 memberedheterocycle substituted with 0-2 R^(1b) and consisting of carbon atomsand 1-2 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(1b), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, methanesulfonyl, C₁₋₄alkyl substituted with 0-3 R^(1c), C₂₋₄alkenylsubstituted with 0-2 R^(1c), aryl substituted with 0-2 R^(1c), 5-6membered heteroaryl substituted with 0-2 R^(1c) and consisting of carbonatoms and 1-2 heteroatoms selected from O, N, and S(O)₀₋₂,C₅₋₆cycloalkyl substituted with 0-2 R^(1c), and a 5-6 memberedheterocycle substituted with 0-2 R^(1c) and consisting of carbon atomsand 1-2 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(1c), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, and C₂₋₄alkenyl, aryl substituted with 0-2 R^(1d), 5-6membered heteroaryl substituted with 0-2 R^(1d) and consisting of carbonatoms and 1-2 heteroatoms selected from O, N, and S(O)₀₋₂,C₅₋₆cycloalkyl substituted with 0-2 R^(1d), and a 5-6 memberedheterocycle substituted with 0-2 R^(1d) and consisting of carbon atomsand 1-2 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(1d), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, and C₂₋₄ alkenyl;

R^(2a) is selected from C₁₋₆alkyl substituted with 0-2 R^(2b), arylsubstituted with 0-2 R^(2b), and 5-6 membered heteroaryl substitutedwith 0-2 R^(2b) and consisting of carbon atoms and 1-2 heteroatomsselected from O, N, and S(O)₀₋₂;

R^(2b), at each occurrence, is selected from OH substituted with 0-1R^(2c), SH, Cl, F, NH₂, —CN, NO₂, methanesulfonyl, C₁₋₄ alkyl, C₂₋₄alkenyl, aryl, 5-6 membered heteroaryl consisting of carbon atoms and1-2 heteroatoms selected from O, N, and S(O)₀₋₂, C₅₋₆cycloalkyl, and a5-6 membered heterocycle and consisting of carbon atoms and 1-2heteroatoms selected from O, N, and S(O)₀₋₂;

R^(2c), at each occurrence, is C₁₋₄ alkyl;

R³ is selected from Cl, F, CH₃, and CH₂ CH₃; and,

alternatively, R³ and R^(5e) combine to form a 5, 6, or 7 membered ringconsisting of carbon atoms and 0-2 heteroatoms selected from O, N, andS(O)₀₋₂ and there are 0-2 ring double bonds in the bridging portionformed by R³ and R^(5e).

10. A compound of clause 8 or 9 wherein:

R¹ is H or C₁₋₄alkyl substituted with 1 R^(1a);

R^(1a), at each occurrence, is selected from aryl substituted with 0-2R^(1b), 5-6 membered heteroaryl substituted with 0-2 R^(1b) andconsisting of carbon atoms and 1-2 heteroatoms selected from O, N, andS(O)₀₋₂, C₅₋₆cycloalkyl substituted with 0-2 R^(1b), and a 5-6 memberedheterocycle substituted with 0-2 R^(1b) and consisting of carbon atomsand 1-2 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(1b), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl substituted with 0-2 R^(1c), C₂₋₄ alkenyl substitutedwith 0-2 R^(1c), aryl substituted with 0-2 R^(1c), 5-6 memberedheteroaryl substituted with 0-2 R^(1c) and consisting of carbon atomsand 1-2 heteroatoms selected from O, N, and S(O)₀₋₂, C₅₋₆cycloalkylsubstituted with 0-2 R^(1c), and a 5-6 membered heterocycle substitutedwith 0-2 R^(1c) and consisting of carbon atoms and 1-2 heteroatomsselected from O, N, and S(O)₀₋₂;

R^(1c), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, and C₂₋₄alkenyl, aryl substituted with 0-2 R^(1d), 5-6membered heteroaryl substituted with 0-2 R^(1d) and consisting of carbonatoms and 1-2 heteroatoms selected from O, N, and S(O)₀₋₂,C₅₋₆cycloalkyl substituted with 0-2 R^(1d), and a 5-6 memberedheterocycle substituted with 0-2 R^(1d) and consisting of carbon atomsand 1-2 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(1d), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, and C₂₋₄alkenyl;

R^(2a) is selected from C₁₋₆ alkyl substituted with 0-2 R^(2b), arylsubstituted with 0-2 R^(2b), and 5-6 membered heteroaryl substitutedwith 0-2 R^(2b) and consisting of carbon atoms and 1-2 heteroatomsselected from O, N, and S(O)₀₋₂;

R^(2b), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, C₂₋₄ alkenyl, aryl, 5-6 membered heteroaryl consistingof carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)₀₋₂,C₅₋₆cycloalkyl, and a 5-6 membered heterocycle and consisting of carbonatoms and 1-2 heteroatoms selected from O, N, and S(O)₀₋₂;

R³ is selected from Cl, F, CH₃, and CH₂ CH₃; and,

alternatively, R³ and R^(5e) combine to form a 5, 6, or 7 membered ringconsisting of carbon atoms and 0-2 heteroatoms selected from O, N, andS(O)₀₋₂ and there are 0-2 ring double bonds in the bridging portionformed by R³ and R^(5e).

11. A compound of clause 8 wherein:

R¹ is H, C₁₋₆alkyl, aryl, 5-6 membered heteroaryl consisting of carbonatoms and 1-2 heteroatoms selected from O and N; C₃₋₁₀ cycloalkyl,wherein each R¹ group is substituted with 0-1 R^(1a);

R^(1a), at each occurrence, is selected from C₁₋₄alkyl substituted with0-3 R^(1b); C₂₋₆alkynyl substituted with 0-1 R^(1b) aryl substitutedwith 0-1 R^(1b), heteroaryl substituted with 0-1 R^(1b), C₅₋₆ cycloalkylsubstituted with 0-1 R^(1b), and a heterocycle substituted with 0-1R^(1b);

R^(1b), at each occurrence, is selected from Cl, F, methanesulfonyl, andC₁₋₄alkyl substituted with 0-3 R^(1c), and;

R^(1c), at each occurrence, is selected from Cl, F and a heterocycle;

R^(2a) is selected from C₁₋₆alkyl substituted with 0-2 R^(2b), arylsubstituted with 0-2 R^(2b), and heteroaryl substituted with 0-2 R^(2b);

R^(2b), at each occurrence, is selected from OH optionally substitutedwith C₁₋₄ alkyl, Cl, F, methanesulfonyl, aryl, heteroaryl,C₅₋₆cycloalkyl, and a heterocycle;

R³ is selected from Cl, F, CH₃, and CH₂ CH₃.

12. A compound of clause 11 wherein:

R¹ is H, C₁₋₆alkyl, aryl, 5-6 membered heteroaryl consisting of carbonatoms and 1-2 heteroatoms selected from O and N; C₃₋₁₀ cycloalkyl,wherein each R¹ group is substituted with 0-1 R^(1a);

R^(1a), at each occurrence, is selected from C₁₋₄alkyl substituted with0-3 R^(1b); C₂₋₆alkynyl substituted with 0-1 R^(1b) aryl substitutedwith 0-1 R^(1b), 5-6 membered heteroaryl substituted with 0-1 R^(1b) andconsisting of carbon atoms and 1-2 heteroatoms selected from O and N,C₅₋₆ cycloalkyl substituted with 0-1 R^(1b), and a 5-6 memberedheterocycle substituted with 0-1 R^(1b);

R^(1b), at each occurrence, is selected from Cl, F, methanesulfonyl, andC₁₋₄alkyl substituted with 0-3 R^(1c), and;

R^(1c), at each occurrence, is selected from Cl, F and a 5-6 memberedheterocycle consisting of carbon atoms and 1-2 heteroatoms selected fromO and N;

R^(2a) is selected from C₁₋₆alkyl substituted with 0-2 R^(2b), arylsubstituted with 0-2 R^(2b), and 5-6 membered heteroaryl substitutedwith 0-2 R^(2b) and consisting of carbon atoms and 1-2 heteroatomsselected from O and N;

R^(2b), at each occurrence, is selected from OH optionally substitutedwith C₁₋₄ alkyl, Cl, F, methanesulfonyl, aryl, 5-6 membered heteroarylconsisting of carbon atoms and 1-2 heteroatoms selected from O and N,C₅₋₆cycloalkyl, and a 5-6 membered heterocycle consisting of carbonatoms and 1-2 heteroatoms selected from O and N;

R³ is selected from Cl, F, CH₃, and CH₂ CH₃.

13. A compound of clause 12 wherein R¹ is C₁₋₄ alkyl substituted with 1R^(1a)

14. A compound of clause 5, wherein the compound is of formula IIb

or a pharmaceutically acceptable salt thereof.

15. A compound of clause 14 wherein R^(2a) is selected from arylsubstituted with 0-2 R^(2b) and 5-6 membered heteroaryl substituted with0-2 R^(2b) and consisting of carbon atoms and 1-2 heteroatoms selectedfrom O, N, and S(O)₀₋₂.

16. A compound of clause 14, wherein R¹ is C₁₋₆ alkyl.

17. A compound of clause 14, wherein R^(2a) is C₁₋₄ alkyl substitutedwith a heterocycle.

18. A compound of clause 14, wherein the R^(2a) is C₁₋₄alkyl substitutedwith morpholinyl.

19. A compound of clause 14, wherein R³ is selected from Cl and CH₃.

20. A compound of clause 14, wherein X is selected from S and SCH₂

21. A compound of clause 14, wherein X is S.

22. A compound of clause 14, wherein X is O.

23. A compound of clause 14, wherein X is SCH₂.

24. A compound of clause 14, wherein X¹ is O.

25. A compound of clause 14, wherein R¹ is aryl substituted with 0-1R^(1a); wherein R^(1a), at each occurrence, is selected from OH, SH, Cl,F, NH₂, —CN, NO₂, C₁₋₄ alkyl.

26. A compound of clause 14, wherein ein R¹ is C₁₋₆ alkyl substitutedwith R^(1a); and wherein R^(1a) is aryl substituted with 0-1 R^(1b); andwherein R^(1b) is selected from OH, SH, Cl, F, NH₂, —CN, NO₂, C₁₋₄alkyl.

27. A compound of clause 14, wherein R¹ is C₁₋₆ alkyl substituted withR^(1a), wherein R^(1a) is heteroaryl substituted with 0-1 R^(1b); andwherein R^(1b) is selected from OH, SH, Cl, F, NH₂, —CN, NO₂, C₁₋₄alkyl.

28. A compound of clause 14, wherein R¹ is C₁₋₆alkyl substituted withR^(1a), wherein R^(1a) is heterocyclyl substituted with 0-1 R^(1b); andwherein R^(1b) is selected from OH, SH, Cl, F, NH₂, —CN, NO₂, C₁₋₄alkyl.

29. A compound of clause 14, wherein R¹ is C₁₋₆ alkyl substituted withR^(1a), wherein R^(1a) is C₅₋₆cycloalkyl substituted with 0-2 R^(1b);and wherein R^(1b) is selected from OH, SH, Cl, F, NH₂, —CN, NO₂, C₁₋₄alkyl.

30. A compound of clause 14, wherein R^(2a) is aryl substituted withR^(2b); wherein R^(2b) is selected from OH, SH, Cl, F, NH₂, —CN, NO₂,C₁₋₄ alkyl.

31. A compound of clause 14, wherein R^(2a) is C₁₋₆ alkyl substitutedwith R^(2b); wherein R^(2b) is selected from aryl substituted withR^(2c); and wherein R^(2c) is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl.

32. A compound of clause 14, wherein R^(2a) is C₁₋₆ alkyl substitutedwith R^(2b); wherein R^(2b) is selected from heteroaryl substituted withR^(2c); and wherein R^(2c) is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl.

33. A compound of clause 1, wherein the compound is selected from:

-   {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(3-piperidin-1-yl-propoxy)-phenylsulfanyl]-phenoxy}-acetic    acid;-   {2-Methyl-4-[3-(3-morpholin-4-yl-propoxy)-5-phenylethynyl-phenylsulfanyl]-phenoxy}-acetic    acid;-   {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(3-morpholin-4-yl-propoxy)-phenylsulfanyl]-phenoxy}-acetic    acid;-   {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(4-morpholin-4-ylmethyl-benzyloxy)-phenyl-sulfanyl]-phenoxy}-acetic    acid;-   {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(1-methyl-piperidin-4-ylmethoxy)-phenylsulfanyl]-phenoxy}-acetic    acid;-   {2-Methyl-4-[3-(3-morpholin-4-yl-propoxy)-5-(3-phenyl-prop-1-ynyl)-phenylsulfanyl]-phenoxy}-acetic    acid;-   {4-[3-(4-Fluoro-benzyloxy)-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   {4-[3-Cyclohexylmethoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   {4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   {4-[3-(4-Chloro-benzyloxy)-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-hydroxy-phenylsulfanyl]-phenoxy}-acetic    acid;-   {4-[3-But-2-ynyloxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   {2-Methyl-4-[3-(2-morpholin-4-yl-ethoxy)-5-phenylethynyl-phenylsulfanyl]-phenoxy}-acetic    acid;-   {2-Chloro-4-[3-(3-methoxy-prop-1-ynyl)-5-(3-morpholin-4-yl-propoxy)-phenylsulfanyl]-phenoxy}-acetic    acid;-   {2-Chloro-4-[3-(3-morpholin-4-yl-propoxy)-5-pent-1-ynyl-phenylsulfanyl]-phenoxy}-acetic    acid;-   {2-Methyl-4-[3-(3-morpholin-4-yl-propoxy)-5-(3-phenyl-prop-1-ynyl)-benzylsulfanyl]-phenoxy}-acetic    acid;

{4-[3-(4-Fluoro-benzyloxy)-5-(3-morpholin-4-yl-prop-1ynyl)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid; and,

-   {2-Methyl-4-[3-(3-morpholin-4-yl-ethoxy)-5-(3-phenyl-prop-1-ynyl)-benzylsulfanyl]-phenoxy}-acetic    acid;    or a pharmaceutically acceptable salt thereof.

34. A compound of clause 1, wherein the compound is selected from:

-   {4-[3-Cyclohexylmethoxy-5-(4-methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   {4-[3-Cyclopentylmethoxy-5-(4-methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   {4-[3-Isobutoxy-5-(4-methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   {4-[3-(2-Ethyl-butoxy)-5-phenylethynyl-phenylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   [4-(3-Cyclopentyloxy-5-phenylethynyl-phenylsulfanyl)-2-methyl-phenoxy]-acetic    acid;-   {4-[3-(4-Fluoro-phenylethynyl)-5-(4-methanesulfonyl-benzyloxy)-phenylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   [4-(3-Cyclopentylmethoxy-5-phenylethynyl-phenylsulfanyl)-2-methyl-phenoxy]-acetic    acid;-   {4-[3-(2-Cyclohexyl-ethoxy)-5-phenylethynyl-phenylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   {4-[3-(2-Ethyl-butoxy)-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   {4-[3-Cyclopentyloxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   {4-[3-(2-Cyclohexyl-ethoxy)-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   {4-[3-Cyclopentylmethoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   {4-[3-Cyclopentylmethoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic;-   {4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-benzylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   [4-(3-Isobutoxy-5-phenylethynyl-benzylsulfanyl)-2-methyl-phenoxy]-acetic    acid;-   {4-[3-Isobutoxy-5-(4-methanesulfonyl-phenylethynyl)-benzylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   {4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(5-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   {4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(3-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-2-methyl-phenoxy}-acetic    acid;-   {2-Methyl-4-[3-(3-morpholin-4-yl-prop-1-ynyl)-5-(3-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-phenoxy}-acetic    acid;-   {2-Methyl-4-[3-(3-morpholin-4-yl-prop-1-ynyl)-5-(5-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-phenoxy}-acetic    acid;-   {2-Methyl-4-[3-(3-morpholin-4-yl-prop-1-ynyl)-5-(3-trifluoromethyl-phenoxy)-phenylsulfanyl]-phenoxy}-acetic    acid;-   {4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(3-trifluoromethyl-phenoxy)-phenylsulfanyl]-2-methyl-phenoxy}-acetic    acid; and-   {2-Methyl-4-[3-phenylethynyl-5-(5-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-phenoxy}-acetic    acid,    or a pharmaceutically acceptable salt thereof.

35. A compound of clause 1, wherein the compound is of formula III:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is C₁₋₄ alkyl substituted with 1-2 R^(1a);

R^(1a), at each occurrence, is selected from aryl substituted with 0-2R^(1b), heteroaryl substituted with 0-2 R^(1b), C₃₋₁₀ cycloalkylsubstituted with 0-2 R^(1b), and a heterocycle substituted with 0-2R^(1b)

R^(1b), at each occurrence, is selected from OH substituted with 0-1R^(1c), SH substituted with 0-1 R^(1c), Cl, F, NH₂ substituted with 0-2R^(1c), —CN, NO₂, C₁₋₄ alkyl substituted with 0-2 R^(1c), C₂₋₄alkenylsubstituted with 0-2 R^(1c), aryl substituted with 0-2 R^(1c),heteroaryl substituted with 0-2 R^(1c), C₃₋₆cycloalkyl substituted with0-2 R^(1c), and a heterocycle substituted with 0-2 R^(1c);

R^(1c), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, and C₂₋₄alkenyl, aryl substituted with 0-2 R^(1d),heteroaryl substituted with 0-2 R^(1d), C₃₋₆cycloal-kyl substituted with0-2 R^(1d), and a heterocycle substituted with 0-2 R^(1d);

R^(1d), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, and C₂₋₄alkenyl;

R^(2a) is selected from aryl substituted with 0-2 R^(2b) and heteroarylsubstituted with 0-2 R^(2b);

R^(2b), at each occurrence, is selected from OH substituted with 0-1R^(2c), SH substituted with 0-1 R^(2c), Cl, F, NH₂ substituted with 0-2R^(2c), —CN, NO₂, C₁₋₄ alkyl substituted with 0-2 R^(2c), C₂₋₄alkenylsubstituted with 0-2 R^(2c), aryl substituted with 0-2 R^(2c),heteroaryl substituted with 0-2 R^(2c), C₃₋₆cycloalkyl substituted with0-2 R^(2c), and a heterocycle substituted with 0-2 R^(2c);

R^(2c), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, C₂₋₄alkenyl, aryl substituted with 0-2 R^(2d), andheteroaryl substituted with 0-2 R^(2d);

R^(2d), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄alkyl, and C₂₋₄alkenyl;

R³ is selected from Cl, F, CH₃, and CH₂ CH₃;

alternatively, R³ and R^(5e) combine to form a 5, 6, or 7 membered ringconsisting of carbon atoms and 0-2 heteroatoms selected from O, N, andS(O)₀₋₂ and there are 0-2 ring double bonds in the bridging portionformed by R³ and R^(5e);

R^(4a), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(4b), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(4c), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(5a), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(5b), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(5c), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(5d), at each occurrence, is selected from H, Cl, F, and CH₃; and,

R^(5e), at each occurrence, is selected from H, Cl, F, and CH₃.

36. A compound of clause 35, wherein:

R¹ is C₁₋₄ alkyl substituted with 1-2 R^(1a);

R^(1a), at each occurrence, is selected from aryl substituted with 0-2R^(1b), 5-10 membered heteroaryl substituted with 0-2 R^(1b) andconsisting of carbon atoms and 1-4 heteroatoms selected from O, N, andS(O)₀₋₂, C₃₋₁₀ cycloalkyl substituted with 0-2 R^(1b), and a 3-8membered heterocycle substituted with 0-2 R^(1b) and consisting ofcarbon atoms and 1-2 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(1b), at each occurrence, is selected from OH substituted with 0-1R^(1c), SH substituted with 0-1 R^(1c), Cl, F, NH₂ substituted with 0-2R^(1c), —CN, NO₂, C₁₋₄ alkyl substituted with 0-2 R^(1c), C₂₋₄ alkenylsubstituted with 0-2 R^(1c), aryl substituted with 0-2 R^(1c), 5-10membered heteroaryl substituted with 0-2 R^(1c) and consisting of carbonatoms and 1-4 heteroatoms selected from O, N, and S(O)₀₋₂,C₃₋₆cycloalkyl substituted with 0-2 R^(1c), and a 3-6 memberedheterocycle substituted with 0-2 R^(1c) and consisting of carbon atomsand 1-2 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(1c), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, and C₂₋₄alkenyl, aryl substituted with 0-2 R^(1d), 5-10membered heteroaryl substituted with 0-2 R^(1d) and consisting of carbonatoms and 1-4 heteroatoms selected from O, N, and S(O)₀₋₂, C₃₋₆cycloalkyl substituted with 0-2 R^(1d), and a 3-6 membered heterocyclesubstituted with 0-2 R^(1d) and consisting of carbon atoms and 1-2heteroatoms selected from O, N, and S(O)₀₋₂;

R^(1d), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄alkyl, and C₂₋₄ alkenyl;

R^(2a) is selected from aryl substituted with 0-2 R^(2b) and 5-10membered heteroaryl substituted with 0-2 R^(2b) and consisting of carbonatoms and 1-4 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(2b), at each occurrence, is selected from OH substituted with 0-1R^(2c), SH substituted with 0-1 R^(2c), Cl, F, NH₂ substituted with 0-2R^(2c), —CN, NO₂, C₁₋₄alkyl substituted with 0-2 R^(2c) C₂₋₄alkenylsubstituted with 0-2 R^(2c), aryl substituted with 0-2 R^(2c), 5-10membered heteroaryl substituted with 0-2 R^(2c) and consisting of carbonatoms and 1-4 heteroatoms selected from O, N, and S(O)₀₋₂,C₃₋₆cycloalkyl substituted with 0-2 R^(2c), and a 3-6 memberedheterocycle substituted with 0-2 R^(2c) and consisting of carbon atomsand 1-2 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(2c), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, C₂₋₄alkenyl, aryl substituted with 0-2 R^(2d), and 5-10membered heteroaryl substituted with 0-2 R^(2d) and consisting of carbonatoms and 1-4 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(2d), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄alkyl, and C₂₋₄ alkenyl;

R³ is selected from Cl, F, CH₃, and CH₂ CH₃;

alternatively, R³ and R^(5e) combine to form a 5, 6, or 7 membered ringconsisting of carbon atoms and 0-2 heteroatoms selected from O, N, andS(O)₀₋₂ and there are 0-2 ring double bonds in the bridging portionformed by R³ and R^(5e);

R^(4a), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(4b), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(4c), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(5a), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(5b), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(5c), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(5d), at each occurrence, is selected from H, Cl, F, and CH₃; and,

R^(5e), at each occurrence, is selected from H, Cl, F, and CH₃.

37. A compound of clause 35, wherein the compound is of formula IIIa

or a pharmaceutically acceptable salt thereof, wherein:

R^(1a), at each occurrence, is selected from aryl substituted with 0-2R^(1b), heteroaryl substituted with 0-2 R^(1b), C₅₋₆cycloalkylsubstituted with 0-2 R^(1b), and a heterocycle substituted with 0-2R^(1b);

R^(1b), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl substituted with 0-2 R^(1c), C₂₋₄alkenyl substitutedwith 0-2 R^(1c), aryl substituted with 0-2 R^(1c), heteroarylsubstituted with 0-2 R^(1c), C₅₋₆cycloalkyl substituted with 0-2 R^(1c),and a heterocycle substituted with 0-2 R^(1c);

R^(1c), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, and C₂₋₄alkenyl, aryl substituted with 0-2 R^(1d),heteroaryl substituted with 0-2 R^(1d), C₃₋₆cycloalkyl substituted with0-2 R^(1d), and a heterocycle substituted with 0-2 R^(1d);

R^(2a) is selected from aryl substituted with 0-2 R^(2b) and heteroarylsubstituted with 0-2 R^(2b) and;

R^(2b), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, C₂₋₄alkenyl, aryl, heteroaryl, C₅₋₆cycloalkyl, and aheterocycle.

38. A compound of clause 37 wherein:

R^(1a), at each occurrence, is selected from aryl substituted with 0-2R^(1b), 5-6 membered heteroaryl substituted with 0-2 R^(1b) andconsisting of carbon atoms and 1-2 heteroatoms selected from O, N, andS(O)₀₋₂, C₅₋₆cycloalkyl substituted with 0-2 R^(1b), and a 5-6 memberedheterocycle substituted with 0-2 R^(1b) and consisting of carbon atomsand 1-2 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(1b), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl substituted with 0-2 R^(1c), C₂₋₄alkenyl substitutedwith 0-2 R^(1c), aryl substituted with 0-2 R^(1c), 5-6 memberedheteroaryl substituted with 0-2 R^(1c) and consisting of carbon atomsand 1-2 heteroatoms selected from O, N, and S(O)₀₋₂, C₅₋₆cycloalkylsubstituted with 0-2 R^(1c), and a 5-6 membered heterocycle substitutedwith 0-2 R^(1c) and consisting of carbon atoms and 1-2 heteroatomsselected from O, N, and S(O)₀₋₂;

R^(1c), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, and C₂₋₄alkenyl, aryl substituted with 0-2 R^(1d), 5-6membered heteroaryl substituted with 0-2 R^(1d) and consisting of carbonatoms and 1-2 heteroatoms selected from O, N, and S(O)₀₋₂, C₃₋₆cycloalkyl substituted with 0-2 R^(1d), and a 3-6 membered heterocyclesubstituted with 0-2 R^(1d) and consisting of carbon atoms and 1-2heteroatoms selected from O, N, and S(O)₀₋₂;

R^(2a) is selected from aryl substituted with 0-2 R^(2b) and 5-6membered heteroaryl substituted with 0-2 R^(2b) and consisting of carbonatoms and 1-2 heteroatoms selected from O, N, and S(O)₀₋₂; and,

R^(2b), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, C₂₋₄alkenyl, aryl, 5-6 membered heteroaryl consistingof carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)₀₋₂,C₅₋₆cycloalkyl, and a 5-6 membered heterocycle and consisting of carbonatoms and 1-2 heteroatoms selected from O, N, and S(O)₀₋₂.

39. A compound of clause 4, wherein:

R¹ is C₁₋₄ alkyl substituted with 1-2 R^(1a);

R^(1a), at each occurrence, is selected from aryl substituted with 0-2R^(1b), heteroaryl substituted with 0-2 R^(1b), C₃₋₁₀ cycloalkylsubstituted with 0-2 R^(1b), and a heterocycle substituted with 0-2R^(1b);

R^(1b), at each occurrence, is selected from OH substituted with 0-1R^(1c), SH substituted with 0-1 R^(1c), Cl, F, NH₂ substituted with 0-2R^(1c), —CN, NO₂, C₁₋₄ alkyl substituted with 0-2 R^(1c), C₂₋₄alkenylsubstituted with 0-2 R^(1c), aryl substituted with 0-2 R^(1c),heteroaryl substituted with 0-2 R^(1c), C₃₋₆cycloalkyl substituted with0-2 R^(1c), and a heterocycle substituted with 0-2 R^(1c);

R^(1c), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, and C₂₋₄alkenyl, aryl substituted with 0-2 R^(1d),heteroaryl substituted with 0-2 R^(1d), C₃₋₆cycloalkyl substituted with0-2 R^(1d), and a heterocycle substituted with 0-2 R^(1d);

R^(1d), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, and C₂₋₄ alkenyl;

R² is aryl substituted with 0-3 R^(2a) or heteroaryl substituted with0-2 R^(2a);

R^(2a), at each occurrence, is selected from OH substituted with 0-1R^(2b), SH substituted with 0-1 R^(2b), Cl, F, NH₂ substituted with 0-2R^(2b), —CN, NO₂, C₁₋₄ alkyl substituted with 0-2 R^(2b), C₂₋₆alkenylsubstituted with 0-2 R^(2b), aryl substituted with 0-2 R^(2b),heteroaryl substituted with 0-2 R^(2b), C₃₋₆cycloalkyl substituted with0-2 R^(2b), and a heterocycle substituted with 0-2 R^(2b);

R^(2b), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄alkyl, and, C₂₋₄ alkenyl;

R³ is selected from Cl, F, CH₃, and CH₂ CH₃;

alternatively, R³ and R^(5e) combine to form a 5, 6, or 7 membered ringconsisting of carbon atoms and 0-2 heteroatoms selected from O, N, andS(O)₀₋₂ and there are 0-2 ring double bonds in the bridging portionformed by R³ and R^(5e);

R^(4a), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(4b), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(4c), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(5a), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(5b), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(5c), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(5d), at each occurrence, is selected from H, Cl, F, and CH₃; and,

R^(5e), at each occurrence, is selected from H, Cl, F, and CH₃.

40. A compound of clause 39, wherein:

R¹ is C₁₋₄ alkyl substituted with 1-2 R^(1a);

R^(1a), at each occurrence, is selected from aryl substituted with 0-2R^(1b), 5-10 membered heteroaryl substituted with 0-2 R^(1b) andconsisting of carbon atoms and 1-4 heteroatoms selected from O, N, andS(O)₀₋₂, C₃₋₁₀ cycloalkyl substituted with 0-2 R^(1b), and a 3-8membered heterocycle substituted with 0-2 R^(1b) and consisting ofcarbon atoms and 1-2 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(1b), at each occurrence, is selected from OH substituted with 0-1R^(1c), SH substituted with 0-1 R^(1c), Cl, F, NH₂ substituted with 0-2R^(1c), —CN, NO₂, C₁₋₄ alkyl substituted with 0-2 R^(1c), C₂₋₄alkenylsubstituted with 0-2 R^(1i), aryl substituted with 0-2 R^(1c), 5-10membered heteroaryl substituted with 0-2 R^(1c) and consisting of carbonatoms and 1-4 heteroatoms selected from O, N, and S(O)₀₋₂,C₃₋₆cycloalkyl substituted with 0-2 R^(1c), and a 3-6 memberedheterocycle substituted with 0-2 R^(1c) and consisting of carbon atomsand 1-2 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(1c), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, and C₂₋₄alkenyl, aryl substituted with 0-2 R^(1d), 5-10membered heteroaryl substituted with 0-2 R^(1d) and consisting of carbonatoms and 1-4 heteroatoms selected from O, N, and S(O)₀₋₂, C₃₋₆cycloalkyl substituted with 0-2 R^(1d), and a 3-6 membered heterocyclesubstituted with 0-2 R^(1d) and consisting of carbon atoms and 1-2heteroatoms selected from O, N, and S(O)₀₋₂;

R^(1d), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄alkyl, and C₂₋₄ alkenyl;

R² is aryl substituted with 0-3 R^(2a) or 5-10 membered heteroarylsubstituted with 0-2 R^(2a) and consisting of carbon atoms and 1-4heteroatoms selected from O, N, and S(O)₀₋₂;

R^(2a), at each occurrence, is selected from OH substituted with 0-1R^(2b), SH substituted with 0-1 R^(2b), Cl, F, NH₂ substituted with 0-2R^(2b), —CN, NO₂, C₁₋₄ alkyl substituted with 0-2 R^(2b), C₂₋₆alkenylsubstituted with 0-2 R^(2b), aryl substituted with 0-2 R^(2b), 5-10membered heteroaryl substituted with 0-2 R^(2b) and consisting of carbonatoms and 1-4 heteroatoms selected from O, N, and S(O)₀₋₂,C₃₋₆cycloalkyl substituted with 0-2 R^(2b), and a 3-6 memberedheterocycle substituted with 0-2 R^(2b) and consisting of carbon atomsand 1-2 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(2b), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄alkyl, and, C₂₋₄alkenyl;

R³ is selected from Cl, F, CH₃, and CH₂ CH₃;

alternatively, R³ and R^(5e) combine to form a 5, 6, or 7 membered ringconsisting of carbon atoms and 0-2 heteroatoms selected from O, N, andS(O)₀₋₂ and there are 0-2 ring double bonds in the bridging portionformed by R³ and R^(5e);

R^(4a), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(4b), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(4c), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(5a), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(5b), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(5c), at each occurrence, is selected from H, Cl, F, and CH₃;

R^(5d), at each occurrence, is selected from H, Cl, F, and CH₃; and,

R^(5e), at each occurrence, is selected from H, Cl, F, and CH₃.

41. A compound of clause 40, wherein the compound is of formula Ib:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is C₁₋₄ alkyl substituted with 1 R^(1a);

R^(1a), at each occurrence, is selected from aryl substituted with 0-2R^(1b), 5-6 membered heteroaryl substituted with 0-2 R^(1b) andconsisting of carbon atoms and 1-2 heteroatoms selected from O, N, andS(O)₀₋₂, C₅₋₆cycloalkyl substituted with 0-2 R^(1b), and a 5-6 memberedheterocycle substituted with 0-2 R^(1b) and consisting of carbon atomsand 1-2 heteroatoms selected from O, N, and S(O)₀₋₂;

R^(1b), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl substituted with 0-2 R^(1c), C₂₋₄alkenyl substitutedwith 0-2 R^(1c), aryl substituted with 0-2 R^(1c), 5-6 memberedheteroaryl substituted with 0-2 R^(1c) and consisting of carbon atomsand 1-2 heteroatoms selected from O, N, and S(O)₀₋₂, C₅₋₆cycloalkylsubstituted with 0-2 R^(1c), and a 5-6 membered heterocycle substitutedwith 0-2 R^(1c) and consisting of carbon atoms and 1-2 heteroatomsselected from O, N, and S(O)₀₋₂;

R^(1c), at each occurrence, is selected from OH, SH, Cl, F, NH₂, —CN,NO₂, C₁₋₄ alkyl, and C₂₋₄alkenyl, aryl substituted with 0-2 R^(1d), 5-6membered heteroaryl substituted with 0-2 R^(1d) and consisting of carbonatoms and 1-2 heteroatoms selected from O, N, and S(O)₀₋₂, C₃₋₆cycloalkyl substituted with 0-2 R^(1d), and a 3-6 membered heterocyclesubstituted with 0-2 R^(1d) and consisting of carbon atoms and 1-2heteroatoms selected from O, N, and S(O)₀₋₂;

R² is aryl substituted with 0-2 R^(2a) or 5-6 membered heteroarylsubstituted with 0-2 R^(2a) and consisting of carbon atoms and 1-2heteroatoms selected from O, N, and S(O)₀₋₂; and,

R^(2a), at each occurrence, is selected from OH substituted with 0-1R^(2b), SH substituted with 0-1 R^(2b), Cl, F, NH₂ substituted with 0-2R^(2b), —CN, NO₂, C₁₋₄ alkyl substituted with 0-2 R^(2b), C₂₋₆alkenylsubstituted with 0-2 R^(2b), aryl substituted with 0-2 R^(2b), 5b-6membered heteroaryl substituted with 0-2 R^(2b) and consisting of carbonatoms and 1-2 heteroatoms selected from O, N, and S(O)₀₋₂,C₅₋₆cycloalkyl substituted with 0-2 R^(2b), and a 5-6 memberedheterocycle substituted with 0-2 R^(2b) and consisting of carbon atomsand 1-2 heteroatoms selected from O, N, and S(O)₀₋₂.

42. A pharmaceutical composition, comprising: a pharmaceuticallyacceptable carrier and a compound of one of clauses 1-41 or apharmaceutically acceptable salt.

43. A pharmaceutical composition for treating type 2 diabetes,comprising a compound according to any of the clauses 1-41 together withone or more pharmaceutically acceptable carriers or excipients.

44. A pharmaceutical composition for treating dyslipidemia, syndrome X(including the metabolic syndrome, e.g., hypertension, impaired glucosetolerance (IGT), insulin resistance, hypertrigyceridaemia, and obesity),cardiovascular diseases (e.g., atherosclerosis and related diseases,including mortality reduction, coronary artery diseases, coronary heartdiseases, heart attack, myocardial ischemia, myocardial infarct,coronary infarct, transient ischemic attack (TIA), and stroke),hyperglycemia, hyperlipidemia, hypercholesterolemia, andhyperinsulinemia, comprising a compound according to any of the clauses1-41 together with one or more pharmaceutically acceptable carriers orexcipients.

45. A pharmaceutical composition for treating dyslipidemia comprising acompound according to any of the clauses 1-41 together with one or morepharmaceutically acceptable carriers or excipients.

46. A pharmaceutical composition for treating syndrome X (including themetabolic syndrome, e.g., hypertension, impaired glucose tolerance(IGT), insulin resistance, hypertrigyceridaemia, and obesity),comprising a compound according to any of the clauses 1-41 together withone or more pharmaceutically acceptable carriers or excipients.

47. A pharmaceutical composition for treating cardiovascular diseases(e.g., atherosclerosis and related diseases, including mortalityreduction, coronary artery diseases, coronary heart diseases, heartattack, myocardial ischemia, myocardial infarct, coronary infarct,transient ischemic attack (TIA), and stroke), comprising a compoundaccording to any of the clauses 1-41 together with one or morepharmaceutically acceptable carriers or excipients

A pharmaceutical composition for treating hyperglycemia comprising acompound according to any of the clauses 1-41 together with one or morepharmaceutically acceptable carriers or excipients.

49. A pharmaceutical composition for treating hyperlipidemia comprisinga compound according to any of the clauses 1-41 together with one ormore pharmaceutically acceptable carriers or excipients.

50. A pharmaceutical composition for treating hypercholesterolemiacomprising a compound according to any of the clauses 1-41 together withone or more pharmaceutically acceptable carriers or excipients

51. A pharmaceutical composition for treating hyperinsulinemiacomprising a compound according to any of the clauses 1-41 together withone or more pharmaceutically acceptable carriers or excipients

52. A pharmaceutical composition according to any one of the clauses42-51 for oral, nasal, transdermal, pulmonal or parenteraladministration.

53. Use of a compound according to any one of the clauses 1-41 as apharmaceutical composition.

54. Use of a compound according to any one of the clauses 1-41 for thepreparation of a pharmaceutical composition for treating type 2diabetes.

55. Use of a compound according to any one of the clauses 1-41 for thepreparation of a pharmaceutical composition for treating dyslipidemia,syndrome X (including the metabolic syndrome, e.g., hypertension,impaired glucose tolerance (IGT), insulin resistance,hypertrigyceridaemia, and obesity), cardiovascular diseases (e.g.,atherosclerosis and related diseases, including mortality reduction,coronary artery diseases, coronary heart diseases, heart attack,myocardial ischemia, myocardial infarct, coronary infarct, transientischemic attack (TIA), and stroke), hyperglycemia, hyperlipidemia,hypercholesterolemia, and hyperinsulinemia.

56. Use of a compound according to any one of the clauses 1-41 for thepreparation of a pharmaceutical composition for treating dyslipidemia.

57. Use of a compound according to any one of the clauses 1-41 for thepreparation of a pharmaceutical composition for treating syndrome X(including the metabolic syndrome, e.g., hypertension, impaired glucosetolerance (IGT), insulin resistance, hypertrigyceridaemia, and obesity).

58. Use of a compound according to any one of the clauses 1-41 for thepreparation of a pharmaceutical composition for treating cardiovasculardiseases (e.g., atherosclerosis and related diseases, includingmortality reduction, coronary artery diseases, coronary heart diseases,heart attack, myocardial ischemia, myocardial infarct, coronary infarct,transient ischemic attack (TIA), and stroke).

59. Use of a compound according to any one of the clauses 1-41 for thepreparation of a pharmaceutical composition for treating hyperglycemia.

60. Use of a compound according to any one of the clauses 1-41 for thepreparation of a pharmaceutical composition for treating hyperlipidemia.

61. Use of a compound according to any one of the clauses 1-41 for thepreparation of a pharmaceutical composition for treatinghypercholesterolemia.

62. Use of a compound according to any one of the clauses 1-41 for thepreparation of a pharmaceutical composition for treatinghyperinsulinemia

63. A method of treating type 2 diabetes, comprising: administering atherapeutically effective amount of a compound of one of clauses 1-41 ora pharmaceutically acceptable salt.

64. A method of treating a disease, comprising: administering atherapeutically effective amount of a compound of one of clauses 1-41 ora pharmaceutically acceptable salt, wherein the disease is selected fromdyslipidemia, syndrome X (including the metabolic syndrome, e.g.,hypertension, impaired glucose tolerance (IGT), insulin resistance,hypertrigyceridaemia, and obesity), cardiovascular diseases (e.g.,atherosclerosis and related diseases, including mortality reduction,coronary artery diseases, coronary heart diseases, heart attack,myocardial ischemia, myocardial infarct, coronary infarct, transientischemic attack (TIA), and stroke), hyperglycemia, hyperlipidemia,hypercholesterolemia, and hyperinsulinemia.

65. A compound of one of clauses 1-41 or a pharmaceutically acceptablesalt thereof, wherein the compound has a solubility in water of at least0.1 mg/L as determined at 25° C. and pH 7.0.

66. The compound of clause 65, wherein the compound has a solubility inwater of at least 0.5 mg/L.

67. The compound of clause 66, wherein the compound has a solubility inwater of at least 1 mg/L.

68. The compound of clause 67, wherein the compound has a solubility inwater of at least 2 mg/L.

69. The compound of clause 68, wherein the compound has a solubility inwater of at least 10 mg/L.

70. The compound of clause 69, wherein the compound has a solubility inwater of at least 50 mg/L.

71. The compound of clause 70, wherein the compound has a solubility inwater of at least 200 mg/L.

72. A compound of one of clauses 1-41 or a pharmaceutically acceptablesalt thereof, wherein the compound has an IC₅₀ value of less than 1 μmas determined by the PPAR transient transactivation assay.

73. The compound of clause 72, wherein the compound has an IC₅₀ value ofless than 500 nm.

74. The compound of clause 73, wherein the compound has an IC₅₀ value ofless than 100 nm.

75. The compound of clause 74, wherein the compound has an IC₅₀ value ofless than 50 nm.

76. The compound of clause 75, wherein the compound has an IC₅₀ value ofless than 25 nm.

77. The compound of clause 76, wherein the compound has an IC₅₀ value ofless than 10 nm.

78. The compound of clause 77, wherein the compound has an IC₅₀ value ofless than 5 nm.

79. A compound of one of clauses 1-41, wherein the compound has amolecular weight of less than 750 g/mol.

80. The compound of clause 79, wherein the compound has a molecularweight of less than 600 g/mol.

81. The compound of clause 80, wherein the compound has a molecularweight of less than 550 g/mol.

82. The compound of clause 81, wherein the compound has a molecularweight of less than 500 g/mol.

83. The compound of clause 82, wherein the compound has a molecularweight of less than 400 g/mol.

84. A compound of one of clauses 1-41, wherein the compound is ionizedat a pH of from 5.5-9.

85. The compound of clause 84, wherein the compound has only one ionizedcarboxylic acid group at a pH of from 6-8.

86. The compound of clause 85, wherein the compound has only one ionizedcarboxylic acid group at a pH of from 6.5-7.5.

87. The compound of clause 86, wherein the compound has only one ionizedcarboxylic acid group at pH 7.4.

88. A compound of one of clauses 1-41, wherein the compound is azwitter-ion with one ionized amine group and one ionized carboxylic acidgroup at a pH of from 5.5-9.

89. The compound of clause 88, wherein the compound is a zwitter-ionwith one ionized amine group and one ionized carboxylic acid group at apH of from 6-8.

90. The compound of clause 89, wherein the compound is a zwitter-ionwith one ionized amine group and one ionized carboxylic acid group at apH of from 6.5-7.5

91. The compound of clause 90, wherein the compound is a zwitter-ionwith one ionized amine group and one ionized carboxylic acid group at pH7.4.

1. A method of treating a renal disease selected from the groupconsisting of glomerulonephritis, glomerulosclerosis, nephroticsyndrome, and hypertensive nephrosclerosis comprising: administering toa human subject{4-[3-isobutoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid or a pharmaceutically acceptable salt thereof.
 2. A method oftreating a renal disease selected from the group consisting ofglomerulonephritis, glomerulosclerosis, nephrotic syndrome, andhypertensive nephrosclerosis comprising: administering to a humansubject{4-[3-isobutoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-benzylsulfanyl]-2-methyl-phenoxy}-aceticacid or a pharmaceutically acceptable salt thereof.
 3. A method oftreating a cardiovascular disease selected from the group consisting ofatherosclerosis, mortality reduction, coronary artery disease, coronaryheart diseases, heart attack, myocardial ischemia, myocardial infarct,coronary infarct, transient ischemic attack (TIA), and strokecomprising: administering to a human subject{4-[3-isobutoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid or a pharmaceutically acceptable salt thereof.
 4. A method oftreating a cardiovascular disease selected from the group consisting ofatherosclerosis, mortality reduction, coronary artery disease, coronaryheart diseases, heart attack, myocardial ischemia, myocardial infarct,coronary infarct, transient ischemic attack (TIA), and strokecomprising: administering to a human subject{4-[3-isobutoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-benzylsulfanyl]-2-methyl-phenoxy}-aceticacid or a pharmaceutically acceptable salt thereof.